Complementary Therapies in Medicine 70 (2022) 102852

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Complementary Therapies in Medicine

journal homepage: www.elsevier.com/locate/ctim

Effect of flaxseed (Linum usitatissimum) supplementation on glycemic

control and insulin resistance in prediabetes and type 2 diabetes: A
systematic review and meta-analysis of randomized controlled trials
Andrea Isabel Villarreal-Renteria a, b, Dulce Daniela Herrera-Echauri c,
Norma Patricia Rodríguez-Rocha b, c, Laura Yareni Zuñiga d, José Francisco Muñoz-Valle a, b,
Samuel García-Arellano a, María Fernanda Bernal-Orozco b, Gabriela Macedo-Ojeda a, b, c, *
a
Institute of Research in Biomedical Sciences (IICB), University Center for Health Sciences (CUCS), University of Guadalajara, 950 Sierra Mojada, ZC 44340
Guadalajara, Jalisco, Mexico
b
Translational Nutritional Sciences, University Center for Health Sciences (CUCS), University of Guadalajara, 950 Sierra Mojada, ZC 44340 Guadalajara, Jalisco
México Guadalajara, Mexico
c
Department of Public Health, University Center for Health Sciences (CUCS) University of Guadalajara, 950 Sierra Mojada, ZC 44340 Guadalajara, Jalisco, Mexico
d
Department of Health and Disease, University Center of Tonala (CUT), University of Guadalajara, 555 Nuevo Periferico, ZC 45425 Tonala, Jalisco, Mexico

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Prediabetes and type 2 Diabetes Mellitus (T2DM) are characterized by increased blood sugar con­
Flax centration and insulin resistance. Although there are only a few reports of potential benefits of flaxseed’s con­
Flaxseed sumption on different metabolic parameters, there is no evidence of its effect among people with these
Linseed
conditions.
Linum usitatissimum
Objectives: The present systematic review and meta-analysis aimed to assess the effect of flaxseed supplemen­
Glycemic control
HbA1c tation on glycemic control variables and insulin resistance in prediabetes and T2DM.
Blood glucose Methods: A literature search was conducted through PubMed, Cochrane Central Register of Controlled Trials
Insulin resistance (CENTRAL), and Web of Science, to identify Randomized Control Trials (RCTs) that evaluated the effect of milled
Type 2 diabetes mellitus or ground flaxseed supplementation on fasting blood glucose, HbA1c, insulin concentrations, or HOMA-IR. The
Prediabetes data were analyzed using Comprehensive Meta-Analysis (CMA) software version 3.3 in a fixed-effect model.
Results: Seven studies were included in the systematic review and the meta-analysis, the results showed a sig­
nificant reduction on fasting blood sugar (SMD: − 0.392, 95% CI: − 0.596, − 0.187, p = <0.001, I2 = 64.81%)
insulin concentrations, (SMD: − 0.287, 95% CI: − 0.534, − 0.041, p = 0.022, I2 = 32.53%), HbA1c (SMD: − 0.442,
95% CI: − 0.770, − 0.114, p = 0.008, I2 = 11.058%), and HOMA-IR (SMD: − 0.284, 95% CI: − 0.530, − 0.038, p =
0.024, I2 = 0.00%) after flaxseed supplementation.
Conclusions: Flaxseed supplementation seems to improve glycemic control variables and insulin resistance in
prediabetes and T2DM; however, more RCTs are needed to have more decisive evidence about doses, method of
supplementation, and the possible effect of synergy with the dietetic treatment.

1. Introduction
Type 2 diabetes mellitus (T2DM) is a disease characterized by defi­
cient insulin secretion by the β-cells of the pancreatic islets and an
impaired sensitivity to insulin, known as insulin resistance. Individuals
who develop this disease gradually increase fasting and postprandial
blood glucose; however, the decrease in insulin sensitivity represents
one of the earliest pathogenic events that begins decades before the
onset of T2DM1. The term "prediabetes" is used to describe glucose
concentration above normal but below the thresholds of T2DM; it is not

* Corresponding author at: Department of Public Health, University Center for Health Sciences (CUCS), University of Guadalajara, 950 Sierra Mojada, ZC 44340
Guadalajara, Jalisco, Mexico.
E-mail addresses: andrea.villarreal@live.com.mx (A.I. Villarreal-Renteria), dulce.echauri@hotmail.com (D.D. Herrera-Echauri), norma.rodriguez@academicos.
udg.mx (N.P. Rodríguez-Rocha), lauray.zuniga@academicos.udg.mx (L.Y. Zuñiga), drjosefranciscomv@cucs.udg.mx (J.F. Muñoz-Valle), samuel.garcia4566@
academicos.udg.mx (S. García-Arellano), fernanda.bernal@academicos.udg.mx (M.F. Bernal-Orozco), gabriela.macedo@cucs.udg.mx (G. Macedo-Ojeda).

https://doi.org/10.1016/j.ctim.2022.102852
Received 30 March 2022; Received in revised form 9 July 2022; Accepted 11 July 2022
Available online 14 July 2022
0965-2299/© 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
A.I. Villarreal-Renteria et al.
a clinical entity, but it is a risk factor for progression to the pathology 2.
The International Diabetes Federation in 2021 estimated a global
T2DM prevalence of 10.5% and projected an increase to 12.2% by 2045,
which represents more than 783 million adults. Diabetes exerts
considerable socioeconomic costs on individual and global health
economies, estimated at 966 billion USD 3. The leading cause of
morbidity and mortality associated with T2DM is cardiovascular dis­
ease. Intensive glucose control is needed to minimize the risk of com­
plications and disease progression 4.
T2DM and prediabetes lead to a greater predisposition to the
development of microvascular and macrovascular complications 5,6. The
Diabetes Control and Complications Trial (DCCT) demonstrated that
glycemic control in patients with T2DM reduced the development of
retinopathy by 76%, and the United Kingdom Prospective Diabetes
Study (UKPDS) reported a 25% reduction in the risk of cardiovascular
complications 7. Moreover, for every 1% decrease in glycated hemo­
globin (HbA1c), the risk of microvascular complications was reduced by
37%. In addition, adequate control reduced the cost associated with the
treatment and long-term management of common complications of
diabetes, leading to the reduction of costs within 5–7 years by reducing
the incidence of future complications 8.
Regarding the treatment of prediabetes and T2DM, there is currently
insufficient evidence to support the use of supplements to improve
glycemic control. However, it is suggested to meet the fiber intake
recommendation through foods naturally rich in dietary fiber as these
foods contain coexisting micronutrients and phytochemicals. Another
recommendation is to consume foods rich in omega-3 fatty acids
through fish, nuts, and seeds 9,10, such as flaxseed.
Flaxseed comes from an herbaceous plant of the Linaceae family
called Linum usitatissimum. It is considered a functional food due to its
attractive nutritional content. In addition to its high dietary fiber con­
tent, proteins and phytoestrogens, it is the most important source of
alpha-linolenic acid (ALA) 11.
Some studies show the benefits of flaxseed supplementation on lipid
profiles, anthropometric measures, and inflammatory cytokines such as
C-reactive protein and interleukin-6 (IL-6) 12–14. In fact, a meta-analysis
demonstrated that whole flaxseed was the most efficient form to
improve glycemic control and insulin resistance; nevertheless, this effect
was not evaluated exclusively in patients with T2DM and prediabetes 15.
Furthermore, to the best of our knowledge, there are no meta-analyses
conducted on patients with prediabetes and T2DM. Therefore, this sys­
tematic review and meta-analysis aims to identify and assess the effect of
flaxseed on glycemic control variables and insulin resistance in these
patients.
2. Methods
2.1. Search strategy
Two researchers (A.I.V.-R. and D.D.H.-E.) conducted an independent
search to identify studies published in three databases without language
and time restrictions until November 1st, 2021, including PubMed, Web
of Science, and the Cochrane Central Register of Controlled Trials
(CENTRAL). The complete search strategy can be consulted in Appendix
A.
The search strategy was performed with combinations of the
following keywords on title and abstract: “flax”, “flaxseed”, “flax-seed”,
“flax seed”, “linum”, “linseed”, “Linum usitatissimum”, “prediabetes”,
“prediabetic”, “prediabetic state”, “diabetes mellitus”, “type 2 diabetes”,
“type 2 diabetes mellitus”, “diabetes or type II”, “diabetes mellitus”,
“haemoglobin A1c”, “hemoglobin A1c”, “glycated hemoglobin”, “gly­
cated haemoglobin”, “glycated hemoglobin”, “HbA1c”, “blood sugar”,
“blood glucose”, “fasting glucose”, “fasting plasma glucose”, “impaired
fasting glucose”, “insulin resistance”, “HOMA-IR”, “HOMA IR”, “ho­
meostasis model assessment”, “glucose tolerance tests”, “oral glucose
tolerance test”, “OGTT” “glucose intolerance”. The results obtained from
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Complementary Therapies in Medicine 70 (2022) 102852
each database were uploaded to the Rayyan Systems Inc. software16,
which was used to complete the selection process of the retrieved
reports.
2.2. Eligibility criteria
The same two researchers independently conducted the selection
process. Studies were included if they were randomized controlled trials
(RCT) performed in patients with T2DM or prediabetes that assessed the
effect of whole or ground flaxseed in glycemic control, insulin, or
HOMA-IR on at least one intervention arm. Studies were excluded if they
had any of the following criteria: (1) animal or in vitro studies, (2)
studies in patients with diseases other than T2DM or prediabetes, (3)
studies in which flaxseed supplementation was combined with another
supplement, (4) studies with children or adolescents, (5) meetings or
conference abstracts, and (6) clinical trials registries. It is worth
mentioning that studies in children and adolescents were excluded
because this age group may have a different response to supplementa­
tion than adults and could require different amounts of flaxseed to
observe a significant change in biochemical indicators. However, it is
important to mention that our search did not identify any studies in
children or adolescents with diabetes or prediabetes in which flaxseed
was supplemented. Any disagreement related to the eligibility of the
studies was discussed between the two investigators to reach a
consensus.
2.3. Data extraction and risk of bias assessment
Data extraction from the articles was performed independently using
digital data collection forms. Extracted data included the year of pub­
lication, the country where it was conducted, sample size, duration,
characteristics of the participants, intervention groups, method of flax­
seed supplementation, outcomes measures, and any other relevant
information.
The risk-of-bias assessment was performed according to the
Cochrane Collaboration with the online tool "Revised Cochrane risk-of-
bias tool for randomized trials (RoB 2)" 17. The studies were classified as
low, high, or unclear risk of bias (some concerns) for five domains, and
finally, an overall score was given to each study.
2.4. Data synthesis and statistical analysis
Previous to performing the statistical analyses, glucose and insulin
units were unified. For glucose, data in mmol/L were multiplied by
18.0182 to obtain mg/dL. To obtain pmmol/L for insulin, the data were
multiplied by 6 for µIU/mL and 6.945 for mU/L. For one article, the
conversion from standard error of mean (SEM) to standard deviation
(SD) was performed by multiplying SEM by the square root of the sample
size 18.
Comprehensive Meta-Analysis (CMA) software version 3.3 was used
for the statistical analysis. The data is presented in a fixed model with
standard differences in means (SMD) and 95% confidence interval (CI).
Heterogeneity was assessed by Cochran’s Q test and quantified using the
I2 statistic. Substantial heterogeneity among studies was assumed when
I2 > 50% and p-value< 0.05.
3. Results of the systematic review
A total of 1208 articles were identified from our initial search (552
from PubMed, 567 from Web of Science, and 89 from CENTRAL); 385
reports were excluded before screening due to duplication. The
remaining 823 records were screened by title and abstract, and 803 were
excluded. The full text of the remaining 20 articles was retrieved, the
final decision on the inclusion of the articles was made based on the
PICOS criteria (appendix A). Finally, after excluding 13 articles for
different reasons, seven studies met the inclusion criteria and were
A.I. Villarreal-Renteria et al.
included in the systematic review and meta-analysis (Fig. 1).
The characteristics of the included studies are shown in Table 1. Of
the seven identified studies, two had a crossover design, all included
adults of both sexes, and the duration of the study in most of them was
12 weeks, except for two, where the treatment duration was eight weeks
19,20
. Three articles were conducted on people with prediabetes and four
on T2DM. The flaxseed consumed in the studies was between 13 and
40 g per day (g/day). The method of supplementation was different in
each study: some of them suggested participants add flaxseed to their
usual meals during the day 19,21; one, to add flaxseed to juices, yogurt, or
water 22, others provided subjects with different baked goods or cookies
with flaxseed 18,23,24, and one, with flaxseed-enriched yogurt 20.
Glycemic control and insulin resistance outcomes of included studies
are shown in detail in Table 2. Flaxseed supplementation in doses from
13 to 40 g significantly improved fasting plasma glucose; the supple­
mentation method varied among studies, such as bread, ground added to
food, or a cookie 21,23,24. The HOMA-IR and insulin concentrations
significantly improved in one study with 13 g of ground flaxseed
compared to the control group 21; another study reported significant
differences within the group that consumed 20 g of flaxseed after
treatment in HOMA-IR 22. The rest of the studies did not find significant
differences. Finally, HbA1c improved in one study with yogurt supple­
mentation containing 30 g of flaxseed 20. None of the identified studies
assessed glucose tolerance with an oral glucose tolerance test.
The results of flaxseed supplementation on glycemic control and
insulin resistance are inconclusive since most studies are too small to
detect differences; therefore, we conducted a meta-analysis to increase
the statistical power and probability of detecting a real effect.
Data are presented as Means and standard deviation (SD). FPG,
Fig. 1. Flow chart of the selection of studies included in the systematic review and meta-analysis.
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Complementary Therapies in Medicine 70 (2022) 102852
fasting plasma glucose; FSG, fasting serum glucose; HOMA-IR, Homeo­
stasis Model Assessment Insulin Resistance; HbA1c, glycated hemoglo­
bin; NR, not reported; NA, not applicable. Values in the same row with
different superscripts are significantly different (p < 0.05).
3.1. Risk of bias assessment
The risk of bias assessment showed that one of the studies had a high
risk 18, five had an unclear risk of bias (some concerns) 19–23, and one
was classified as low risk of bias 24 (Fig. 2).
One study had an unclear risk of bias in the first domain due to
significant differences between baseline fasting blood sugar, insulin, and
HOMA-IR, suggesting a problem with the randomization process 22. In
the second domain, four studies had unclear risk (some concerns)
because there is no information on whether caregivers and intervention
providers were aware of the intervention assigned to participants during
the trial 18,19,21,22. In the third domain, one study had an unclear risk of
bias due to missing complete results of insulin and HOMA-IR 23, and
another study mentioned that there were dropouts because patients did
not want to cooperate. However, they did not indicate whether it refers
to the consumption of supplementation 20. Concerning the fourth
domain, all studies had an unclear risk of bias; one study did not mention
the methodology used to determine fasting plasma glucose, HbA1c, and
insulin levels 18. One study cited another article that could not be
retrieved through manual search 23. The rest did not report whether
researchers conducting the data analyses were blinded to the partici­
pant’s group. Finally, one study was classified with an unclear risk of
bias in the fifth domain since sub-analyses were performed "because
there were no significant main effects" 18.
A.I. Villarreal-Renteria et al. Complementary Therapies in Medicine 70 (2022) 102852

Table 1
Characteristics of included studies.
Author (year Country RCT Sample Gender Mean BMI kg/ Duration of Condition Intervention Administration
of design size/ age m2 (SD) intervention groups
publication) dropouts (SD)

Rhee et al. United Crossover 11/2 W= 5 M= 4 54.7 (6.6) 32.4 (8.2) 12 weeks Prediabetes 1) Wheat bran: In the form of ground
(2011)23 States 40 g grain or bread in
2) Flaxseed: 40 g their daily meals,
using a method of
their choice.
Hutchins United Crossover 41/16 W= 14 58.6 (6.3) 30.4 (5.3) 12 weeks Prediabetes 1) Control: no Ground flaxseed as
et al. States M= 11 intervention part of meals and
(2013)21 2) Low dose: snacks with the
13 g indication of not to
3) High dose: bake, cook, or
26 g microwave
Javidi et al. Iran Parallel 99/7 W= 40 -Control: -Control: 12 weeks Prediabetes 1) Control: no Milled flaxseed to
(2016)22 M= 52 50.5 26.6 (3.76) intervention take along with their
(11.5) -Low dose: 2) Low dose: meal in yogurt, milk,
-Low dose: 28.87 20 g juice, or water
52.9 (8.9) (3.96) 3) High dose:
-High -High dose: 40 g
dose: 27.87
52.1 (3.61)
(9.15)
Taylor et al. Canada Parallel 34/0 W= 17 52.4 (1.5) 32.4 (1.0) 12 weeks Well- 1) Control: In bakery products:
(2013)18 M= 17 Controlled bakery products muffins, scones,
T2DM 2) Milled crispbread, crackers,
flaxseed: 32 g in snack bars,
bakery products pancakes, waffles,
3) Flaxseed oil: and pizza crust
13 g in bakery
products
Ricklefs et al. United Parallel 19/2 W= 8 -Flaxseed: -Flaxseed: 8 weeks T2DM 1) Psyllium: 9 g Distributed
(2016)19 States M= 9 59.7 (7.9) 31.7 (4.2) 2) Flaxseed: 28 g throughout the day
-Psyllium: -Psyllium: as participants
58.5 (9.4) 29.0 (6.7) wished
Soltanian Iran Parallel 81/4 W= 13 -Placebo: -Placebo: 12 weeks Constipated 1) Placebo: Pre-mixed in sugar-
et al. M= 64 55.9 (8.7) 28.7 (5.9) patients with maltodextrin free, orange-flavored
(2018)24 -Flaxseed: -Flaxseed: T2DM cookies cookies. Two cookies
55.7 29.1 (3.8) 2) Flaxseed: 10 g two times per day as
(11.6) -Psyllium: pre-mixed in a snack
-Psyllium: 29.3 (5.2) sugar-free
58.0 (7.2) cookies
3) Psyllium:
10 g pre-mixed
in sugar-free
cookies
Hasaniani Iran Parallel 70/13 W= 37 -Control: -Control: 8 weeks T2DM 1) Control: No specified
et al. M= 21 52.5 (6.0) 29.5 (3.9) 200 g/day plain
(2019)20 -Flaxseed: -Flaxseed: yogurt per day
54.1 (5.4) 29.3 (3.4) 2) Flaxseed:
200 g 2.5% fat
yogurt
containing 30 g
flaxseed

RCT, Randomized control trial; SD, Standard Deviation; BMI, Body Mass Index, W, Woman; M, men; T2DM, Type 2 Diabetes Mellitus.

3.2. Results of the effect of flaxseed supplementation on fasting blood
sugar
The meta-analysis of nine datasets showed a significant reduction in
fasting blood sugar after flaxseed supplementation in patients with
prediabetes and T2DM (SMD: − 0.392, 95% CI: − 0.596 to − 0.187,
p = <0.001), a large heterogeneity between-study was found (Q=22.73,
p < 0.004, I2= 64.81%) (Fig. 3).
Potential sources of heterogeneity were assessed in a subgroup
analysis by condition (prediabetes and T2DM) and by flaxseed dose (low
dose <25 g and high dose >25 g), with no significant differences be­
tween subgroups (Table 3).
3.3. Results of the effect of flaxseed supplementation on HbA1C
HbA1C concentrations after flaxseed supplementation in patients with
T2DM (SMD: − 0.442, 95% CI: − 0.770 to − 0.114, p = 0.008) a low
heterogeneity between-study was found (Q=3.372, p = 0.338, I2=
11.058%) (Fig. 4).
3.4. Results of the effect of flaxseed supplementation on insulin
concentrations
The meta-analysis of six datasets showed a significant reduction in
insulin concentrations after flaxseed supplementation in patients with
prediabetes and T2DM (SMD: − 0.287, 95% CI: − 0.534 to − 0.041,
p = 0.022) a low heterogeneity between-study was found (Q=8.194,
p = 0.146, I2= 32.53%) (Fig. 5).

The meta-analysis of four datasets showed a significant reduction in

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A.I. Villarreal-Renteria et al. Complementary Therapies in Medicine 70 (2022) 102852

Table 2
Glycemic control and insulin resistance outcomes of included studies.
Study Outcome Baseline Final Δ Baseline Final Δ Baseline Final Δ
23
Rhee et al. (2011) Intervention 40 g wheat bran 40 g flaxseed NA
groups
a b
FPG mg/dL 102.1 (2.5) 103.2 (6.3) NR 106.6 (5.5) 86.3 (3.0) NR NA NA NA
Insulin No significant differences between groups (No numeric data reported) NA NA NA
HOMA-IR No significant differences between groups (No numeric data reported) NA NA NA
Hutchins et al. Intervention Control 13 g of flaxseed 26 g of flaxseed
(2013)21 groups
FPG mg/dL 105.0 113.0 (19.0) 8.0 (21.0)a 112.0 (17) 110.0 (17) − 2.0 112.0 113.0 1.0 (12.0)a, b
(22.0) (8.0)b (18.0) (18.0)
Insulin pmol/L 65.2 (29.8) 79.1 (56.2) 13.8 (47.2)a 79.8 (45.8) 66.6 (36.1) − 13.8 72.9 79.8 6.9 (29.8)a
(32.6)b (32.6) (49.3)
HOMA-IR 2.5 (1.2) 3.1 (2.0) 0.7 (1.8)a 3.2 (1.9) 2.6 (1.4) − 0.7 2.9 3.3 0.4 (1.2)a
(1.5)b (1.4) (2.0)
Javidi et al. (2016)22 Intervention Control 20 g of flaxseed 40 g of flaxseed
groups
a
FSG mg/dL 104.6 (4.8) 96.8 (13.7) -7.8 (12.1) 109.3 (7.6) 100.6 (15.1) -8.6 110.0 99.7 -10.3
(13.7)a (7.2) (17.8) (16.2)a
Insulin pmol/L 29.4 (24.8) 32.2 (28.2) − 2.8 72.4 (78.1) 62.3 (78.3) -10.0 45.1 47.1 − 1.9
(15.7)a (33.6)a (61.9) (53.5) (40.1)a
HOMA-IR 0.8 (0.4) 0.8 ± (0.4) -0.01 (0.3)a 1.5 (1.5) 1.3 (1.3) -0.2 1.1 1.0 -0.09
(0.6)a (1.2) (1.1) (0.79)a
Taylor et al. (2013)10 Intervention Control 32 g of flaxseed 13 g flaxseed oil
groups
a
FPG mg/dL 138.7 135.1 (5.4) NR 118.9 117.5 (6.5)a NR 124.3 126.1 NR
(10.8) (12.9) (12.4) (6.2)a
HbA1C % 7.0 (0.3) 7.2 (0.3)a NR 6.3 (0.3) 6.3 (0.3)a NR 6.5 6.7 NR
(0.3) (0.3)a
Insulin pmol/L 152.0 166.0 NR 148.0 136.0 NR 168.0 165.0 NR
(33.0) (18.0)a (32.4) (18.0)a (31.1) (17.3)a
HOMA-IR 7.9 (1.8) 8.0 (0.9)a NR 6.5 (1.8) 6.0 (1.08)a NR 7.6 7.7 NR
(1.7) (1.03)a
19
Ricklefs et al. (2016) Intervention 28 g of flaxseed 9 g psyllium NA
groups
FPG mg/dL 119.5 134.9 (55.1) 15.4 (24.9)a 130.7 129.1 (69.1) -1.6 NA NA NA
(32.7) (62.2) (37.0)a
HbA1C % 7.1 (1.5) 6.6 (1.1) -0.5 (0.8)a 6.7 (2.0) 6.8 (2.6) 0.1 NA NA NA
(0.6)a
a
Insulin pmol/L 81.6 (22.2) 105.0 (46.8) 24.0 (34.2) 87.6 (34.8) 115.2 (81) 27.6 NA NA NA
(67.2)a
HOMA-IR 4.1 (1.6) 6.3 (4.1) 2.2 (3.1)a 5.0 (3.1) 6.7 (6.6) 1.8 NA NA NA
(6.0)a
Soltanian et al. (2018)[ Intervention Placebo 20 g of flaxseed 20 g of psyllium
groups
a
FPG mg/dL 165.6 163.7 (39.5) -1.9 (27.9) 164.8 137.0 (26.4) -27.8 167.0 147.3 -19.7
(43.5) (45.2) (31.0)b (38.2) (43.0) (29.4)b
a
HbA1C % 8.0 (2.2) 9.0 (2.2) 1.0 (2.3) 8.4 (2.0) 7.7 (2.0) -0.7 8.5 7.7 -0.8 (2.1)a
(1.6)a (2.1) (2.1)
Hasaniani et al. Intervention Control 30 g of flaxseed NA
(2019)20 groups
FPG mg/dL 139.3 154.1 (52.5) 25.2 (36.6)a 114.1 118.3 (26.7) 4.2 NA NA NA
(50.1) (33.6) (26.03)a
HbA1C % 7.3 (1.5) 7.1 (1.59) − 0.15 6.4 (1.1) 6.1 (1.0) − 0.3 NA NA NA
(1.0)a (0.3)b

3.5. Results of the effect of flaxseed supplementation on HOMA-IR

The meta-analysis of six datasets showed a significant reduction in

HOMA-IR concentrations after flaxseed supplementation in patients
with T2DM (SMD: − 0.284, 95% CI: − 0.530 to − 0.038, p = 0.024) a low
heterogeneity between-study was found (Q=3.632, p = 0.603, I2=
0.00%) (Fig. 6).

4. Discussion

The current meta-analysis showed that flaxseed supplementation

Fig. 2. Risk of bias assessment of included studies using Cochrane criteria.
significantly improves fasting blood sugar concentrations, HbA1c, in­
sulin, and HOMA-IR in patients with prediabetes and T2DM. All analyses
showed low heterogeneity, except the effect on the fasting blood sugar
analysis, which subgroup analysis could not explain.
These results align with those reported previously in a meta-analysis
where different forms of flaxseed supplementation (flaxseed oil, lignans,

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A.I. Villarreal-Renteria et al. Complementary Therapies in Medicine 70 (2022) 102852

Fig. 3. Forest plot for the effect of flaxseed supplementation on fasting blood sugar.

Table 3
Subgroup analyses for the effects of flaxseed supplementation on glycemic control and insulin resistance in patients with prediabetes and T2DM.
Outcome Subgroups Number of effect sizes SMD 95% CI I2 p-value between groups

Fasting blood glucose Prediabetes 5 -0.355 -0.617, − 0.092 80.56 0.666

T2DM 4 -0.449 -0.776, − 0.122 0.000
Low dose 3 -0.434 -0.631, − 0.090 73.62 0.726
High dose 6 -0.360 -0.747, − 0.121 45.32

SMD, standard mean difference; CI, confidence interval; T2DM, Type 2 Diabetes Mellitus.

Fig. 4. Forest plot for the effect of flaxseed supplementation on HbA1c.

Fig. 5. Forest plot for the effect of flaxseed supplementation on insulin concentrations.

or ground flaxseed) were compared in glycemic control among different
pathologies and healthy individuals. This analysis found that supple­
mentation with ground flaxseed was the most effective way to supple­
ment flaxseed 15. However, the effects of supplementation, specifically
in patients with prediabetes and T2DM, had not been explored. There­
fore, to the best of the author’s knowledge, this is the first meta-analysis
to evaluate the effects of whole or ground flaxseed supplementation on
glycemic control and insulin resistance in this type of patients.
Flaxseed’s potential mechanisms of action on glucose metabolism
and insulin resistance may be due to its bioactive compounds such as
ALA, secoisolariciresinol diglucoside (SDG), and fiber 11. The lipid
content of flaxseed is approximately 73%, of which 32–45% is ALA,
making it the primary source of this omega-3 11,25–27. This fatty acid is a
precursor for docosahexaenoic acid (DHA) and eicosapentaenoic acid
(EPA), which have anti-inflammatory properties. However, although the
rate of conversion to EPA and DHA is shallow 28, in some studies, it has
been observed that higher ALA content in adipose tissue is inversely
related to insulin resistance in healthy adults; since it could reduce the

6
A.I. Villarreal-Renteria et al.
Fig. 6. Forest plot for the effect of flaxseed supplementation on HOMA-IR.
secretion of Tumor Necrosis Factor-alpha (TNF-α), IL-6, Interleukin-1
beta (IL-1β), and monocyte chemoattractant protein-1 and improve in­
sulin sensitivity in this tissue 29. In serum, it has even been proposed as a
biomarker of T2DM progression and may also have a protective role in
developing the disease 30,31.
On the other hand, one-third of the fiber content of flaxseed is soluble
fiber 11. The proposed mechanism through which soluble fiber has
anti-diabetic effects is increasing chyme viscosity, delaying gastric
emptying, delaying sugar and nutrients absorption in the small intestine.
This stimulates the release of Glucagon-Like Peptide-1 (GLP-1), a pep­
tide that significantly decreases appetite, increases pancreatic beta-cell
growth, and improves insulin production 32.
Moreover, flaxseed is the most important source of SDG, a phytoes­
trogen compound known for its beneficial effects on oxidative stress,
cardiovascular disease, inflammation, cancer, and diabetes. The exact
mechanism has not been well described, but its benefits have been
attributed to its antioxidant properties 33.
Patients with prediabetes and T2DM often have other cardiovascular
risk factors, such as hypertension and dyslipidemia. Flaxseed supple­
mentation can lower serum lipoprotein (a), a premature risk factor for
cardiovascular disease and blood pressure, proving evidence that the
benefit of flaxseed consumption goes beyond glycemic control 34–36.
In future RCTs, the mentioned mechanisms of flaxseed compounds
that improve glycemic control should be studied using the whole seed,
as it is necessary to generate knowledge about functional foods and the
best form of consumption when added to the diet of patients with pre­
diabetes and T2DM. How flaxseed was supplemented in the studies
included in this review differed among them. Most involved adding
ground flaxseed to foods such as juices, milk, bakery products, and
yogurt, which may be one of the main weaknesses of the studies and why
the effect sizes are modest, as these foods may have an impact on par­
ticipants’ glycemic control variables. No study combined flaxseed sup­
plementation with dietary recommendations or exercise, which are the
cornerstones of the treatment for these patients.
Thus, new studies are needed to evaluate the effect of flaxseed in
combination with the already well-established dietetic treatment, with
attention to how it is supplemented to avoid foods with high sugar
content and therefore assess the synergistic effect of this seed with the
current recommendations on glycemic control. Similar to what was
carried out in an RCT in patients with metabolic syndrome in which one
of the intervention arms supplemented 30 g of milled flaxseed dissolved
in 250 mL of water along with lifestyle modification for 12 weeks and
showed a significant reduction in serum triglycerides concentrations and
insulin resistance 37.
A potential limitation observed in the studies included in this meta-
analysis is related to the difficulties to blind the participants and the
personnel, something common in most nutritional intervention studies,
which leads to a risk of bias. Also, most of the studies had a limited
sample size, and the amount of flaxseed supplemented was different in
each study.
This systematic review showed that 13–40 g of flaxseed could
7
Complementary Therapies in Medicine 70 (2022) 102852
significantly improve fasting blood sugar,13 g improved insulin con­
centrations and HOMA-IR, and 30 g improved HbA1c. In this meta-
analysis, the effect of a low dose (<25 g) and a high dose (>25 g) of
flaxseed were explored, but there were no significant differences be­
tween these groups. Hence, with the current information is not possible
to conclude which is the most effective dose for flaxseed
supplementation.
Therefore, it is necessary to design new studies that consider previ­
ously described limitations to reach more solid conclusions on the use of
flaxseed for glycemic control in adults with prediabetes and diabetes.
5. Conclusion
The current findings show that supplementation with ground flax­
seed significantly improves fasting blood sugar, HbA1C, insulin con­
centrations, and HOMA-IR in patients with prediabetes and T2DM.
However, more studies are needed to identify the optimal doses, eval­
uate the seed’s effect by itself without incorporating foods rich in sugars
or carbohydrates into the diet, and studies that evaluate the possible
effect in synergy with the dietetic treatment.
Funding
This work was developed with a grant from the Fund for Scientific
Development of Jalisco to address state problems (FODECIJAL) 2019,
project number 8177–2019.
Declarations of interest
None.
CRediT authorship contribution statement
Andrea Isabel Villarreal-Renteria: Conceptualization, Methodol­
ogy, Formal analysis, Investigation, Writing – original draft. Dulce
Daniela Herrera-Echauri: Methodology, Investigation, Data curation,
Writing – original draft. Norma Patricia Rodríguez-Rocha: Method­
ology, Formal analysis, Writing – review & editing. Laura Yareni
Zuñiga: Conceptualization, Resources, Writing – review & editing, Su­
pervision. José Francisco Muñoz-Valle: Conceptualization, Resources,
Writing – review & editing. Samuel García-Arellano: Methodology,
Data curation, Writing – review & editing. María Fernanda Bernal-
Orozco: Conceptualization, Methodology, Writing – review & editing.
Gabriela Macedo-Ojeda: Conceptualization, Formal analysis, Writing –
review & editing, Project administration.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
A.I. Villarreal-Renteria et al.
Appendix A. Supporting information
Supplementary data associated with this article can be found in the
online version at doi:10.1016/j.ctim.2022.102852.
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