Critical Reviews in Food Science and Nutrition

ISSN: 1040-8398 (Print) 1549-7852 (Online) Journal homepage: http://www.tandfonline.com/loi/bfsn20

The effects of supplementation with conjugated

linoleic acid on anthropometric indices and body
composition in overweight and obese subjects: A
systematic review and meta-analysis

Nazli Namazi, Pardis Irandoost, Bagher Larijani & Leila Azadbakht

To cite this article: Nazli Namazi, Pardis Irandoost, Bagher Larijani & Leila Azadbakht (2018):
The effects of supplementation with conjugated linoleic acid on anthropometric indices and body
composition in overweight and obese subjects: A systematic review and meta-analysis, Critical
Reviews in Food Science and Nutrition, DOI: 10.1080/10408398.2018.1466107

To link to this article: https://doi.org/10.1080/10408398.2018.1466107

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Apr 2018.

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Publisher: Taylor & Francis
Journal: Critical Reviews in Food Science and Nutrition
DOI: https://doi.org/10.1080/10408398.2018.1466107

The effects of supplementation with conjugated linoleic acid on

anthropometric indices and body composition in overweight and obese

subjects: A systematic review and meta-analysis

Nazli Namazi1, Pardis Irandoost2, Bagher Larijani3*, Leila Azadbakht4, 5, 6*

1
Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular-
Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
2
Department of Nutrition, School of Public Health, Iran University of Medical Sciences,
Tehran, Iran
3
Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical
Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
4
Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute,
Tehran University of Medical Sciences, Tehran, Iran
5
Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran
University of Medical Sciences, Tehran, Iran
6
Department of Community Nutrition, School of Nutrition and Food Science, Isfahan
University of Medical Sciences, Isfahan, Iran

Corresponding Authors:

Leila Azadbakht, PhD

Department of Community Nutrition
School of Nutritional Sciences and Dietetics
Tehran University of Medical Sciences
Tehran, PO Box: 1416643931
Iran
Tel: (+98) 218895556
2

Fax: (+98) 2188984861

Email: [email protected]

Bagher Larijani, MD, Endocrinologist

Endocrinology and Metabolism Research Center
Endocrinology and Metabolism Clinical Sciences Institute
Tehran University of Medical Sciences
Tehran, PO Box: 1411413137
Iran

Tel: (+98) 218822003

Fax: (+98) 2188220052; Email: [email protected]
ABSTRACT

Clinical trials have indicated conflicting results on the effects of conjugated linoleic acid (CLA)

on obesity. The present study aimed to systematically review controlled clinical trials examining

the effects of CLA on anthropometric indices and body composition in overweight and obese

subjects. Pubmed, Scopus, Web of science, and Cochrane databases were searched between 2000

and December 2017 with no language restriction. Placebo-controlled clinical trials that reported

anthropometric indices and body composition in overweight and obese subjects were included.

Random-effect model was used to pool the effect estimates. Of 4032 publications, 13 trials were

included for the meta-analysis. Pooled effect sizes indicated that CLA significantly reduced body

weight (WMD: -0.52 kg, 95% CI: -0.83, -0.21; I2: 48.0%, p=0.01), BMI (WMD: -0.23 kg/m2,

95% CI: -0.39, - 0.06; I2: 64.7%, p=0.0001), FM (WMD: -0.61 kg, 95% CI: -0.98, -0.24; I2:

53.8%, p=0.01) and increased LBM (WMD: 0.19 kg, 95% CI: 0.04, 0.34; I2: 81.4%, p=0.0001)

compared to the placebo group. However, the effects of CLA on WC (WMD: 0.05 cm, 95% CI: -

0.01, 0.1; I2: 0%, p=0.93) was not significant. Additionally, its impact on body weight in subjects

older than 44 year (WMD: -1.05 kg, 95% CI: -1.75, -0.35; I2: 57.0%, p=0.01), with longer

duration (more than 12 weeks) (WMD: -1.29 kg, 95% CI: -2.29, -0.29; I2: 70.3%, p=0.003) and

dosage more than 3.4 g/day (WMD: -0.77 kg, 95% CI: -1.28, -0.25; I2: 62.7%, p=0.004) were
3

greater than comparative groups. Supplementation with CLA can slightly reduce body weight

and FM and increase LBM in overweight and obese subjects. However, its efficacy was not

clinically relevant. Further studies with high methodological quality are needed to shed light on

the effects of CLA on anthropometric indices in overweight and obese subjects.

Keywords: CLA, Obesity, WC, body composition

INTRODUCTION

Obesity is one of main public health problem that is growing dramatically across the world (1).

Different weight management strategies including adherence to weight loss diets, increasing

physical activity levels, changing in dietary habits and other lifestyle modifications have been

introduced (2). However, a demand to identify an anti-obesity agent to reduce dietary restrictions

with minimum changes in usual life style has been existed (3). A wide range of supplements and

medications are available with the claim of slimming effects; Nevertheless, the efficacy for

numbers of them has not been proven yet (4). One of such supplements is conjugated linoleic

acid (CLA) (5).

CLA is a group of positional and geometrical isomers of linoleic acid (C18:2, n-6), which are

linked by the presence of conjugated dienes (5). Cis-9, trans-11 CLA and trans-10, cis-12 CLA

are examples of the main active isomers (6). CLA is produced naturally and is found in fat, milk

and meat of ruminant animals (7). Based on prior studies, CLA posses beneficial properties such

as anti-carcinogenic effects, improving insulin resistance, glucose levels, lipid profile, blood

pressure, body composition and weight (8, 9). However, anti-obesity effects of CLA are

controversial.
4

Several possible mechanisms have been suggested for anti-obesity effects of CLA in animal

models (10-15) and human studies (16-20). For instance, it can decrease the size of adipocytes,

modify adipocyte differentiation, stimulate apoptotic pathways and regulate lipid metabolism (5).

Several narrative reviews and meta-analysis have been published earlier in this regard (5, 21-23).

The meta-analysis by Kim et al., revealed that supplementation with CLA could reduce body

weight and body mass index (BMI) significantly, whereas its effects were not clinically relevant

(5). In the study by Kim et al., the efficacy of CLA on body composition and other

anthropometric indices including waist and hip circumferences were not examined. Additionally,

they only included studies on metabolic syndrome (MetS) and its efficacy on subjects without

chronic diseases remained unclear. Another meta-analysis by Onakpoya et al., evaluated only

long-term (more than 6 months) effects of CLA in overweight and obese subjects (24). Although

they found a significant reduction in body weight and fat mass (FM), they stated that due to

differences in the methodology of the included studies more clinical trials are needed to clarify

its effects on obesity. They also did not compare short- and long-term effects of CLA on obesity.

Currently, there is no convincing evidence for nutritionists to recommend CLA as a

complementary therapy along with a low-calorie diet for overweight and obese individuals.

Accordingly, we aimed to summarize the short- and long-term effects of CLA on anthropometric

indices and body composition in overweight and obese subjects as a systematic review and meta-

analysis.

METHOD

We followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA)

guidelines for the present systematic review and meta-analysis (25).

5

Literature search and study identification: A systematic search was conducted using PubMed,

Scopus, Web of Sciences and Cochrane electronic databases to identify clinical trials that

examined the effects of CLA supplement on anthropometric indices and body composition from

January 2000 to December 2017 without language restriction. Additionally, hand-searching from

reference lists of all relevant papers, previous reviews and meta-analyses was performed to cover

all relevant publications. The primary outcome was body weight and other outcomes of interest

included BMI, waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WtHR),

fat mass (FM), and lean body mass (LBM).

To create a strategy search, a combination of the MeSH (Medical Subject Headings) terms from

the PubMed database and free text words were used. For each electronic database, search

strategy was adopted. For example, the search strategy for the PubMed were as follows:

(“conjugated linoleic acid” [tiab] OR “conjugated fatty acid” [tiab] OR “bovic acid” [tiab] OR

“rumenic acid” [tiab] OR “CLA” [tiab]) AND (“weight”[tiab] OR “obes*” [tiab] OR “body

composition” [tiab] OR “adiposity” [tiab] OR “slim” [tiab] OR “waist” [tiab] OR “abdomen”

[tiab] OR “BMI” [tiab] OR “body mass index” [tiab]). PubMed‟s e-mail alert service was

activated to identify any new publication in this regard after the search. Details of the search

strategy for other databases are presented in Appendix 1.

The protocol of the study was registered in the international prospective register of systematic

reviews (PROSPERO) database (http://www.crd.york.ac.uk/PROSPERO; registration number:

CRD42018085447).

Inclusion and exclusion criteria: To be included in the systematic review and meta-analysis, a

publication had to meet the following criteria: (i) placebo-controlled clinical trials (both parallel
6

and cross-over studies); (ii) CLA as a supplement; (iii) adult subjects (older than 18 years); (iv)

reporting at least body weight before and after the study; (v) providing sufficient information on

anthropometric indices (body weight, BMI, WC) and body composition (FM, FFM) with

standard deviations (SDs), standard errors of the means (SEMs), or 95% confidence intervals

(CIs) at baseline and at the end of intervention in the intervention and placebo group.

We did not include (i) before-after studies or any other human models except clinical trial; (ii)

animal or in vitro studies; (iii) CLA-enriched food; (4) CLA in combination with other

ingredients; (iv) subjects with any disease and (v) children. Grey literature including conference

abstract, thesis, and reports due to problems in access and insufficient data were excluded as

well. PICOS criteria are presented in Table 1.

Two independent reviewers (N.N, L.A) searched the databases and screened the publications to

reach possible relevant papers. Any disagreement was solved by discussion.

Data extraction: The following data based on a pre-designed form were extracted from each

paper by two reviewers (N.N, P.I) independently: name of first author, publication year, country,

individual‟s characteristics including mean age, sex, randomization, blinding (open label, single

or double blind), sample size (enrollment, completion), dosage, duration of intervention, other

intervention, and outcome values at the beginning and at the end of study. When more than one

paper from the same study individuals was published, data from the publications with the largest

and the longest duration of the intervention were extracted. If there were more than two study

groups, only the data for CLA group (s) and placebo were extracted. Studies in which the interest

outcomes were reported in more than two intervals, only data at baseline and at the end of the

intervention were extracted. Some studies examined different dosages of CLA; in such studies
7

each dosage considered as an independent study by dividing sample size into numbers of

assessed dosages to avoid multiple counting. As in most studies, FM and LBM were reported in

gram, this type of reporting data were included in the meta-analysis. When our necessary data

were not reported in the papers, we contacted the authors by emails for three times in reasonable

intervals. When we did not receive any answer, we excluded the whole of the paper or variable

with insufficient information.

Risk of bias assessment: Two reviewers (N.N, P.I) independently examined the risk of bias for

the included studies using the Cochrane quality assessment tool for RCTs (26). This checklist

has 7 criteria for quality assessment including: (i) random sequence generation, (ii) allocation

sequence concealment, (iii) blinding of participants and personnel, (iv) blinding of outcome

assessment, (v) incomplete outcome data, (vi) selective outcome reporting, and (vii) other

potential sources of bias. Low risk of bias, high risk of bias, or being unclear for each aforesaid

item was determined. Any disagreement in the all aforementioned processes which were not

resolved through consultation was referred to the principal reviewer (L.A) in order to reach a

consensus.

Quantitative data synthesis and statistical analysis: Effect sizes for all interest outcomes were

expressed as weighted mean differences (WMDs) and 95% CI. The effect sizes were pooled

using a random effects model with DerSimonian and Laird method (27). Wherever within-group

changes did not report, mean value at the end of the study was subtracted from the mean at the

baseline in each group. To calculate the SD, the following formula was used: SD= square root

[(SD pre-treatment) 2 + (SD post-treatment) 2 – (2R × SD pre-treatment × SD post-treatment)]. In

this formula, R=0.5 was assumed as a correlation coefficient which ranges between 0 and 1 (28).

When an SEM was reported instead of SD, based on the following formula, SD was calculated:
8

SD= SEM× square root (n), that „n‟ was sample size in each group. If the outcome values were

reported in medians and ranges or 95% CIs, means and SD values were estimated using the

method by Hozo et al., (29). Plot digitizer software was used to obtain the data when the

outcome was presented only in the graphic form.

Heterogeneity was assessed by the I2 index; I2 greater than 50% was considered as the existence

of substantial heterogeneity among the studies (30). To identify factors for high heterogeneity,

whenever possible (at least two studies in each subgroup), subgroup analysis was performed.

A pre-defined subgroup analysis was based on the following parameters: mean age, sex, dosage,

duration of supplementation, and quality assessment. Less or more than median was considered

as cut off values for each aforementioned quantitative parameter for subgroup analysis.

The sensitivity analysis was performed using the leave-one-out method (removing a single

clinical trial in each time and repeating the analysis) to examine the impact of each trial on the

pooled effect size. Any potential publication bias was identified using the funnel plot, either

Egger‟s regression test (number of studies less than 10) or Begg‟s rank correlation (number of

studies more than 10). When a publication bias was existed, “trim and fill” method was used to

correct the overall effect size. All statistical analyses were carried out using STATA version 11.0

(Stata Corp, College Station, TX). P values that were less than 0.05 were considered statistically

signifcant.

Results

Selection and characteristics of the included studies: As presented in Figure 1, a total of 4032

publication (including 1855 duplications) were initially identified after searching Pubmed,

Scopus, Web of science, and Cochrane electronic databases. Of 2177 publications, 2130 were

excluded after screening based on title and abstract. They were irrelevant to the current meta-
9

analysis according to our criteria. In the next step, 47 possible relevant papers were selected for

the evaluation of full-texts. After detailed examination, 31 papers were excluded due to the

following reasons: Irrelevant (n=3), unhealthy patients (n=8), children (n=1), did not report body

weight or other necessary data (n=2), repeated data (n=3), studies on athletes (n=2), not

supplement (n= 6), do not have placebo (n= 4), in combination with other components (n=2).

In the last procedure, a total of 16 eligible RCTs were included. As the authors of three studies

did not provide us necessary data (not answered our emails (n=2), not access of authors to data

(n=1)), they were excluded. Finally, 13 clinical trials were included for the meta-analysis.

Characteristics of the included studies: Characteristics of the 13 randomized clinical trials (6,

16-20, 31-37) are reported in Table 2. The sample size in the included trials ranged from 18 (16)

to 394 (19). The included studies were published between 2000 and 2016 and were conducted in

the USA (n=3) (6, 17, 18), Europe (n= 8) (16, 19, 20, 31-33, 35, 37), and Asia (n=2) (34, 36).

The mean age of the participants ranged from 23 (20) to 58 (19) years. Trials included men

(n=2) (35, 36), women (n=3) (20, 34, 37) and both genders (n=9) (6, 16-19, 31-33).

In four studies (16, 20, 32, 36), either a special diet or physical activity program were

recommended along with CLA supplementation. The dosage of CLA was between 1.5 (35) and

6.8 g/day (16) and it was consumed from 8 (20, 36) to 52 (32) weeks. In the all included studies

(6, 16-20, 31-37), a mixture of CLA isomers (particularly cis 9, trans 11 isomer in combination

with trans 10, cis 12) was recommended.

Most studies (n=7) (16, 17, 20, 31-33, 35) used olive oil as a placebo. The remaining papers used

safflower oil (n=3) (6, 18, 19), sunflower (n=2) (34, 37), soybean (n=1) (36). All studies except

two (used body impedance analyzer), used dual-energy X-ray absorptiometry (DEXA) for

measurement of body compositions.

10

Gastrointestinal problems including nausea, stomachache, burning and frequent bowel

movement, bloating, soft stool, constipation and other side effects such as headache, eczema and

backache were also reported. They were mild to moderate. However, in 5 studies drop out was

reported due to the side effects following CLA supplementation (16, 17, 20, 31, 34). In the all

mentioned studies except one (34), the drop out was 1 due to adverse effects. However,

Darestani et al., reported 4 drop outs following taking CLA with dosage of 3.2 g/day. All studies

except one (37) had high risk of bias based on the Cochrane criteria. Therefore, all findings

should be declared with more caution.

Systematic review: Limited studies reported the effects of CLA on hip circumference (HC)

(n=3) (17, 32, 37) and WtHR (n=2) (17, 19). Madry et al indicated that daily 3gr CLA reduced

HC significantly (-2cm) after 12 weeks of supplementation (37). However, based on Larsen et

al., 3.4 g/day CLA did not change HC after 8 weeks (32). In the study by Gaullier et al., although

a reduction in HC and WtHR was observed in the intervention group, the changes were not

significant between two groups (38). Besides, Slujis et al found that CLA did not have positive

effect on reduction in WtHR in overweight and obese subjects (19). Due to limited studies on

HC and WtHR, meta-analysis was not performed on this regard.

Meta-analysis for the effects of supplementation with CLA on anthropometric indices:

Forest plots for the effects of CLA on anthropometric indices (body weight, BMI and WC) are

presented in Figures 2-4.

Body weight: As our primary outcome was body weight, all the 13 included studies (6, 16-20,

31-37) reported weight changes following the CLA supplementation. Pooled effect sizes

indicated that CLA significantly reduced body weight (WMD: -0.52 kg, 95% CI: -0.83, -0.21; I2:

48.0%, p=0.01) compared to placebo (Figure 2). Subgroup analysis indicated that reduction in
11

body weight in older individuals (more than 44 year old) (WMD: -1.05 kg, 95% CI: -1.75, -0.35;

I2: 57.0%, p=0.01) was significantly greater that the younger one (less than 44 years old) (WMD:

-0.07 kg, 95% CI: -0.29, 0.15; I2: 0%, p=0.84). Dosage more than 3.4 g/day WMD: -0.77 kg,

95% CI: -1.28, -0.25; I2: 62.7%, p=0.004) reduced body weight significantly more than the lower

one (WMD: -0.16 kg, 95% CI: -0.43, 0.12; I2: 0%, p=0.59). However, it also did not attenuate

the heterogeneity. Reduction in body weight after longer duration (more than 12 weeks) (WMD:

-1.29 kg, 95% CI: -2.29, -0.29; I2: 70.3%, p=0.003) of the intervention was significantly greater

than the shorter duration (less than 12 weeks) (WMD: -0.09 kg, 95% CI: -0.30, 0.12 I2: 0%,

p=0.96) of the supplementation. Stratification by risk of bias, life style interventions, and sex did

not reduce the between-study heterogeneity. However, subgroup analysis based on control group

(olive oil, sunflower oil) considerably removed the heterogeneity (I2:0%) (Table 3). Among the

included studies, only one recommended a low-calorie diet along with CLA, after removing this

study, no considerable changes were observed in body weight (WMD: -0.53 kg, 95% CI: -0.85, -

0.22, I2: 50.8%, p=0.007).

BMI: Twelve trials (6, 16, 17, 19, 20, 31, 33-37) provided data on the effects of CLA on BMI

(Figure 3). The pooled estimates demonstrates that supplementation with CLA significantly

reduced BMI in healthy subjects (WMD: -0.23 kg/m2, 95% CI: -0.39, - 0.06), while the

heterogeneity was high (I2: 64.7%, p=0.0001). Stratification by duration showed a greater

reduction in BMI following longer duration (WMD: -0.51 kg/m2, 95% CI: -0.92, -0.09; I2:

80.5%, p=0.0001), while it was not significant after the shorter one (WMD: 0.05 kg, 95% CI: -

0.05, 0.15; I2: 0%, p=0.73). After excluding one study with high risk of bias no considerable

changes in the pooled estimate was observed (WMD: -0.29 kg, 95% CI: -0.45, -0.12; I2: 70.1%,

p=0.0001). After removing one study (37) with high risk of bias, the pooled estimates did not
12

change notably (WSD: -0.23 kg/m2, 95% CI: -0.39, -0.06; I2:64.7%, p=0.0001). The results of

other stratifications by sex, placebo type and dosage were presented in Table 3.

Waist circumference: The results for WC were shown in 7 RCTs (19, 20, 32, 34-37) including

8 effect sizes. Overall, supplementation with CLA did not significantly change WC compared to

placebo group (WMD: -0.05 kg, 95% CI: -0.01, 0.1; I2: 0%, p=0.93) (Figure 4). As no

heterogeneity was existed, we did not perform subgroup analysis for WC.

Meta-analysis for the effects of supplementation with CLA on body composition

Fat mass: The pooled estimates of FM (7 studies, 12 effect sizes) (6, 16-18, 31, 32, 34) showed

that in subjects who consumed CLA, FM decreased significantly compared to those in placebo

group (WMD: -0.61 kg, 95% CI: -0.98, -0.24; I2: 53.8%, p=0.01) (Figure 5). Longer

intervention by CLA resulted in greater reduction in FM (WMD: -1.94 kg, 95% CI: -2.74, -1.15;

I2: 0%, p=0.58), while FM changes was -0.23 kg (95% CI: -0.25, -0.21; I2: 0%, p=0.77) after

shorter supplementation. Stratification by duration removed the heterogeneity considerably

compared to other parameters. Additionally, CLA reduced FM in older subjects (WMD: -1.79

kg, 95% CI: -2.72, -0.86; I2: 0%, p=0.49) significantly more than younger ones (WMD: -0.32 kg,

95% CI: -0.56, -0.08; I2: 46.9 %, p=0.11) (Table 3). After removing one study (32) that

recommended CLA along with diet, the reduction in FM remained significant (WMD: -0.62 kg,

95% CI: -1.01, -0.24; I2: 57.9 %, p=0.008).

Lean body mass: The pooled estimate (containing 9 effect sizes extracted from 5 RCTs) (6, 16,

17, 31, 34) for LBM is presented in Figure 6. Based on findings, significant changes were

observed in LBM following the CLA supplementation (WMD: 0.19 kg, 95% CI: 0.04, 0.34; I2:

81.4%, p=0.0001). After removing one study (17) which examined long-term effects of CLA, the

heterogeneity was reduced considerably (WMD: 0.32 kg, 95% CI: 0.16, 0.48; I2: 0%, p=0.99).
13

Stratification by mean age revealed that LBM in younger can significantly enhance LBM

(WMD: 0.31 kg, 95% CI: 0.16, 0.47; I2: 0%, p=0.97), while the changes were not significant in

older one (WMD: -0.28 kg, 95% CI: -2.20, 1.64; I2: 46.8%, p=0.09) (Table 3).

In three trials (6, 16, 35) more than one dosage of CLA was examined. After considering only

the highest dosage of each study in the meta-analysis, we found that CLA reduced body weight

(WMD: -0.72 kg, 95% CI: -1.13, -0.31; I2: 52.4%, p=0.01), BMI (WMD: -0.30 kg, 95% CI: -

0.49, -0.11; I2: 64.5%, p=0.01), FM (WMD: -0.36 kg, 95% CI: -0.67, -0.05; I2: 0%, p=0.49) with

no changes in LBM (WMD: -0.15 kg, 95% CI: -1.17, 1.44; I2: 90.3%, p=0.0001) and WC

(WMD: 0.05 kg, 95% CI: -0.01, 0.10; I2: 0%, p=0.87) in overweight and obese subjects.

Publication bias

Based on visual inspection of funnel plots, there was no publication bias in the effects of CLA on

anthropometric indices and body composition that were confirmed by complementary analyses.

Begg's test indicated no publication bias for body weight (p=0.75), BMI (p=0.99), FM (p=0.10),

and LBM (p=0.11). Egger test also confirmed no publication bias for WC (p=0.17).

Sensitivity analysis: According to sensitivity analysis, excluding none of the trials had a

considerable change on body weight (range= -0.23 to -0.36), BMI (range= -0.21, -0.33), WC (-

0.05, 0.09), and FM (range= -0.21, -0.25). However, leave-one-out method did not show the

robustness in findings of LBM (range= -1.16, 0.09)”.

Discussion

Based on the current systematic review and meta-analysis, supplementation with CLA can

significantly but slightly reduce body weight, BMI and FM and increase LBM in overweight and

obese subjects. However, its effects on WC were not statistically significant.

14

Our findings were in line with earlier meta-analysis (24) which examined the long-term (more

than 6 months) effects of CLA in overweight and obese subjects. Based on pooling effect

estimates of 6 RCTs, they found that CLA can reduce body weight (-0.7 kg) and FM (-1.3 kg)

without changes in WC (-0.12 cm). In our study, we included all available studies (n=13) in this

regard without any limitation in the duration of intervention. In our meta-analysis, the mean

period of supplementation was 3 months. Observing similar findings with Onakpoya et al., study

(24) can show no considerable differences in the efficacy of CLA in different duration of

supplementation. Hence, limited studies (n=7) were included in the meta-analysis by Onakpoya

et al, subgroup analysis based on study and participants᾽ characteristic were not possible.

Another meta-analysis is the study by Kim et al (5). Our findings were in parallel with Kim et

al., study. They reported that CLA reduced body weight (-0.5 kg) and BMI (-0.18 kg/m2) (5).

However, they did not examine either WC or body composition. In contrary to our study that

only healthy subjects (without any disease except obesity) were included, they examined subjects

with MetS. Similar results can show that the efficacy of CLA is not affected by metabolic status

and disease background. Due to limited studies in Kim et al.᾽s meta-analysis (5), subgroup

analysis were not performed. Our findings were also similar to Rahbar et al.᾽s study. They

indicated that neither CLA supplement nor foods enriched with CLA changed WC in healthy

adults (39).

Our findings revealed that CLA with 3.4 g/day or greater, in subjects older than 44 years for

minimum 12 weeks had the highest effect on body weight. However, supplementation for the

mean duration of 12 weeks resulted in only 1.3 kg reduction in body weight that it was too slight

from clinical point of view. Although BMI reduction following receiving CLA was statistically

significant, it was not clinically relevant. Based on our findings, short-term supplementation did
15

not lower BMI value. Most included studies did not recommend subjects to increase their

physical activity or reduce their energy intake. However, findings indicated no significant

differences between studies with and without other weight management strategies.

We found that CLA is not considerably helpful for improving body size and body composition.

Although more than 12- week supplementation reduced FM by 2 kg, it is moderate from clinical

point. Besides, CLA is not much effective in increasing LBM and only in younger subjects a

slight increase was observed. In the present study, we did not include RCTs on athletes due to

their different physiological and metabolic characteristics. Therefore, the efficacy of CLA on

body composition of this group remained unclear. Hence, reduction in LBM may result in a

reduction in basal metabolic rate; LBM maintenance can be helpful for preventing weight regain

(40). However, in the present meta-analysis, weight reduction following CLA was small and

observing no changes in LBM might be due to this issue. Overall, due to limited studies on WC,

FM, LBM, findings of the aforesaid variables and their stratifications by parameters that may

affect the results should be declared with caution.

Based on prior clinical trials on weight management (41-43), weight-loss diet with even a

moderate physical activity is more effective than CLA supplementation. Based on findings, CLA

did not reduce at least 5% of body weight at the end of the trial compared to the baseline. In our

meta-analysis, most included studies recommended CLA alone not with low-calorie diets or

exercise; Therefore, CLA concurrent with other common weight-loss treatment can be more

helpful. However, more evidence is needed to confirm this hypothesis.

Several possible mechanisms are suggested for CLA on anthropometric indices and body

composition. CLA can impact upon lipoprotein lipase, stearoyl coenzyme A desaturase, activate

Peroxisome proliferator-activated receptor gamma (PPAR-γ) receptors and pro-inflammatory

16

cytokines (6, 44). Accordingly, it can reduce fat accumulation (24). In addition, animal studies

showed that CLA particularly trans-10, cis-12 isomer can reduce energy intake, inhibit

lipogenesis, and increase fat oxidation (44). Some studies demonstrated that CLA can cause

insulin resistance (45, 46) and this adverse effect is more probable in older obese individuals

(47); however, this issue is conflicting. Different isomers of CLA had different effects.

Therefore, observing different findings on the effects of CLA can be partially interpreted by this

matter. For instance, trans-10, cis-12 showed catabolic effects, increase in lipolysis and fat

oxidation, while cis-9, trans-11 plays an anabolic role (33).

Another plausible mechanism of CLA on obesity is related to its impacts on hormones. Based on

evidence, CLA can decrease leptin hormone following a reduction in FM (17). It also can

increase serum levels of adiponectin, a hormone with anti-inflammatory properties (46, 48). In

the present meta-analysis, limited studies examined the effects of CLA on serum levels of leptin

(17, 18, 33). Serum levels of leptin in Macredmond et al., decreased with no considerable

changes in adiponectin levels (33). However, Gauiller et al., found no changes in leptin and

adiponectin concentrations following the CLA intervention (38). Additionally, based on Watras

et al., changes in leptin levels were not significant after 6 months of the intervention (18).

Increasing energy expenditure through changes in gene expression (ex. encoding uncoupling

proteins), reduction in adipocyte size, inhibiting pre-adipocyte differentiation and increasing

adipocyte apoptosis are reported for CLA (6).

It is notable that the type of placebo is the main parameter in RCTs. Apart from its appearance

(color, size) that is recommended to be similar to the intervention; it should have minimum effect

on interest outcomes. In our meta-analysis, the included studies reported different materials as a

placebo including olive, sunflower, soybean, palm oil, oleic acid and safflower oil. Stratification
17

by the type of placebo revealed different findings. For instance, reduction in body weight

following CLA compare to olive oil showed the greatest value compare to other placebo groups.

Another important point in RCTs is related to the side effects of the intervention. In our meta-

analysis, a few studies reported drop out due to severe gastrointestinal disorders or other

complications following CLA supplementations (16, 17, 20, 31, 34). Although CLA is not an

effective anti-obesity supplement, no serious side effects at least in the reported ranges of dosage

were observed. However, gastrointestinal disorders were reported in most studies in a few

participants.

The findings of the present meta-analysis can be helpful for nutritionists and researchers.

However, it had some limitations. First, we could not compare the pure effects of CLA verses its

concurrent use with a low-calorie diet due to limited studies. Second, as most studies

recommended a mixture of CLA isomers, the most effective one or a suitable isomer

combination remained unclear. The strength of the current meta-analysis was as follows: (i)

examining CLA on overweight and obese subjects without any disease background that might

affect the results, (ii) pooling suitable numbers of RCTs made it possible to do subgroup

analysis, and (iii) examining the risk of bias that can affect the effect estimates. However, as

most studies had a high risk of bias, making decision on the efficacy of CLA on obesity should

be declared with caution.

In conclusion, supplementation with CLA can slightly reduce body weight, BMI and FM and

increase LBM in overweight and obese subjects. However, its efficacy was not clinically

relevant. More studies with high methodological quality are required to clarify the efficacy of

CLA on obesity management. Due to the lack of robustness in the effects of CLA on LBM,

drawing a decisive conclusion needs further investigations in this regard. For future studies,
18

examining the efficacy of CLA on body composition in athletes and weight maintenance is

suggested.

Author Contribution statement: The authors‟ responsibilities were as follows: B.L, L.A

designed the research; N.N and P.I: conducted systematic research; P.I, N.N: extracted data;

N.N, L.A, B.L: analyzed data; N.N, B.L and L.A: wrote manuscript; N.N, L.A: had primary

responsibility for the final content of the manuscript; and all authors read and approved the final

manuscript. None of the authors reported a conflict of interest related to the study.

Acknowledgment

We would like to express our sincere thanks to Iran National Science Foundation (grant number:

95013061) and Endocrinology & Metabolism Research Institute, Tehran University of Medical

Sciences for their financial support.

19

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24

Legends to figures:

Figure 1- Flowchart for study identification and selection

25
26

Figure 2- Forest plot of weighted mean difference (WMD) in body weight between
supplementation with CLA and placebo group
27

Figure 3- Forest plot of weighted mean difference (WMD) in body mass index between
supplementation with CLA and placebo group
28

Figure 4- Forest plot of weighted mean difference (WMD) in waist circumference between
supplementation with CLA and placebo group
29

Figure 5- Forest plot of weighted mean difference (WMD) in fat mass between
supplementation with CLA and placebo group
30

Figure 6- Forest plot of weighted mean difference (WMD) in lean body mass between
supplementation with CLA and placebo group
31

Table 1- The PICO criteria used for the present systematic review

PICO criteria Description

Patients Overweight OR obese subjects

Exposure “conjugated linoleic acid” OR “conjugated fatty acid” OR “bovic acid”

OR “rumenic acid” OR “CLA”

Comparison Placebo

Outcome “Weight” OR “BMI” OR “body mass index” OR “waist circumference” OR

“fat mass” OR “FM” OR “lean body mass” OR “LBM”
32

Table 2- Characteristics of the included studies in the meta-analysis

Author/ Countr Subject Me Sam Study Other Dosa Durat Side Qual
Year y an ple design interven ge ion effects ity
(gende age size (Blindi tion
r) (yea ng) (g/da (wk) (withdra
r) y) wal due
to side
effects)

Madry et Poland Female 54 62 R/P No 3 12 Nausea High

al, 2016
Double (n=0)
(37)

Pina et Brazil Female 23 28 R/P 3.2 8 Gastrointe Low

al, 2016 stinal
(20) Double Aerobic discomfort
training , stomach
program ache,
burning
and more
frequent
bowel
movement
s

(n=1)

Tajmanes Iran Male 24.8 66 R/P Physical 3.2 8 Not Low

h et al, activity reported
Double program
2015 (36) (n=0)

DeGuire Canada Male 37.5 21 R/P Two Gastrointe Low

et al, differ stinal
2012 (35) Double No ent 16 discomfort
dosag (n=0)
es:

1.5

MacRed Canada Male & 31 26 R/P No 4.5 12 Headache, Low

mond et Female Backache
al, 2010 Double Gastrointe
33

(33) stinal
upset

(n=0)

Sluijs et Netherl Male & 58.4 346 R/P No 4 24 Gastrointe Low

al, 2010 ands Female stinal
(19) Double discomfort
,

Eczema,

Transpirati
on, Heart

complaints

(n=0)

Darestani Iran Menop 55.1 67 R/P No 3.2 12 Gastrointe Low

et al, ause stinal
Double discomfort
2010 (34) female
(n=4)

E. Steck U.S Male & 35.1 48 R/P No Two 12 Mild Low

et al, Female differ gastrointes
2007 Double ent tinal
dosag adverse
(6) events
es:
Gas,
3.2
Bloating,
Indigestio
6.4
n,
Diarrhea,
or
Heartburn
(increase
in higher
dose)

(n=0)

Watras et U.S Male & 33.1 40 R/P No 3.2 24 Not Low

al, 2007 Female reported

(18) Double

Gaullier Norway Male & 47.1 105 R/P 3.4 24 Constipati Low
et al, on
34

2007 Female 8 Double No (n=0)

(38)

Larsen et Norway Male & 42.5 77 R/P Modest 3.4 52 Soft Low
al, 2006 Female 1 hypocal stools,
(32) Double oric diet Depressio
n,
Air in the
stomach,
or
Stomach
pain

(n=0)

Berven et Norway Male & 47.0 47 R/P No 3.4 12 Diarrhea, Low

al, 2000 Female 8
Double Bad oral
(31)
smell,

Bad smell
of
perspiratio
n

(n=1)

Blankson Norway Male & 45.4 47 R/P Standard Four 12 Gastrointe Low
et al, Female 7 training differ stinal
Double program ent discomfort
2000 (16) dosag (n=1):dose
es: 6.8g/day

1.7

3.4

5.1

6.8

Replace
their
habitual
lunch by
one meal
of a
protein-
35

rich,
low-

energy
supplem
ent

*Randomized placebo
36

Table 3- Subgroup analysis for the effects of CLA on anthropometric indices and body
composition

Outcome No.study Pooled effect size I2 (%) P heterogeneity P between

(95% CI)

Body weight

Age

> 44 years 6 -1.05 (-1.75, -0.35) 57 0.01 0.001

≤ 44 years 7 -0.07 (-0.29, 0.15) 0 0.8

Sex

Men 2 0.11 (-2.60, 2.82) 0 0.94 0.85

Women 3 -0.58 (-1.31, 0.14) 0 0.73

Both 8 -0.59 (-0.96, -0.21) 64.3 0.001

Duration

>12 weeks 5 -1.29 (-2.29, -0.29) 70.3 0.003 0.001

≤ 12 weeks 8 -0.09 (-0.30, 0.12) 0 0.96

Dose

> 3.4 g/day 7 -0.77 (-1.28, -0.25) 62.7 0.004 0.04

≤ 3.4 g/day 8 -0.16 (-0.43, 0.12) 0 0.59

Physical
activity
program

Yes 3 -0.87 (-3.25, 1.51) 0 0.98 0.72

No 10 -0.56 (-0.90, -0.21) 64.5 0.001

Type of
Control

Olive oil -1.92 (-2.64, -1.19) 0 0.98

37

Sunflower oil -0.56 (-1.29, 0.17) 0 0.50 0.001

Safflower oil -0.26 (-0.59, 0.08) 79.4 0.002

BMI

Age

> 44 years 6 -0.42 (-0.71, -0.12) 67.1 0.002 0.001

≤ 44 years 7 0.07 (-0.03, 0.17) 0 0.46

Sex

Men 2 -0.02 (-0.85, 0.81) 0 0.94 0.76

Women 3 -0.24 (-0.53, 0.05) 0 0.80

Both 7 -0.25 (-0.45, -0.06) 76.6 0.0001

Duration

>12 weeks 5 -0.51 (-0.92, -0.009) 80.5 0.0001 0.0001

≤ 12 weeks 8 0.05 (-0.05, 0.15) 0 0.73

Dose

> 3.4 g/day 6 -0.33 (-0.58, -0.09) 73.8 0.0001 0.009

≤ 3.4 g/day 8 -0.10 (-0.34, 0.13) 25.9 0.21

Physical
activity
program

Yes 3 -0.30 (-0.99, 0.39) 0 0.98 0.64

No 10 -0.23 (-0.41, -0.05) 76.7 0.0001

Type of
Control

Olive Oil 6 -0.73 (-0.98, -0.48) 0 0.97 0.001

Sunflower oil 3 -0.23 (-0.53, 0.06) 0 0.54

FM
38

Age

> 44 years 4 -1.79 (-2.72, -0.86) 0 0.49 0.001

≤ 44 years 4 -0.32 (-0.56, -0.08) 46.9 0.11

Duration

>12 weeks 4 -1.94 (-2.74, -1.15) 0 0.58 0.0001

≤ 12 weeks 3 -0.23 (-0.25, -0.21) 0 0.77

Dose

> 3.4 g/day 5 -1.45 (-2.59, -0.31) 53.1 0.03 0.12

≤ 3.4 g/day 4 -0.63 (-1.69, 0.39) 53.8 0.09

Type of
Control

Olive oil 4 -2.14 (-3.09, -1.19) 0 0.94 0.0001

Safflower oil 2 -0.31 (-0.56, -0.07) 65.4 0.05

LBM

Age

> 44 years 2 -0.28 (-2.20, 1.64) 46.8 0.09 0.0001

≤ 44 years 5 0.31 (0.16, 0.47) 0 0.97

 39

Appendix 1- Search strategies and the number of publications in each electronic database

Database Search strategy Number

of
publicati
ons

PubMed ("conjugated linoleic acid"[tiab] OR "conjugated fatty acid"[tiab] OR "rumenic 740

acid"[tiab] OR "CLA"[tiab]) AND ("weight"[tiab] OR "obes*"[tiab] OR "body
composition"[tiab] OR "adiposity"[tiab] OR "slim"[tiab] OR "waist"[tiab] OR
"abdomen"[tiab] OR "BMI"[tiab] OR "body mass index"[tiab]) AND
2000/01/01:2017/12/31 [dp]
Web of ((TS= (“conjugated linoleic acid”) OR TS= (“conjugated fatty acid”) OR TS= 1845
Science (“bovic acid”) OR TS= (“rumenic acid”) OR TS= (“CLA”)) AND (TS= (weight)
OR TS= (obesity) OR TS= (obese) OR TS= (“body composition”) OR TS=
(“adiposity”) OR TS= (“slim”) OR TS= (waist) OR TS= (“abdomen”) OR TS=
(“BMI”) OR TS= (“body mass index”)) AND (PY= (1990-
2017))) AND DOCUMENT TYPES: (Article)
Scopus TITLE-ABS ( "conjugated linoleic acid" ) OR TITLE-ABS ( "conjugated fatty 1322
acid" ) OR TITLE-ABS ( "rumenic acid" ) OR TITLE-
ABS ( "CLA" ) AND ( TITLE-ABS ( "weight" ) OR TITLE-
ABS ( "obese" ) OR TITLE-ABS ( obesity ) OR TITLE-ABS ( "body
composition" ) OR TITLE-ABS ( "adiposity" ) OR TITLE-
ABS ( "slim" ) OR TITLE-ABS ( "waist" ) OR TITLE-
ABS ( "abdomen" ) OR TITLE-ABS ( "BMI" ) OR TITLE-ABS ( "body mass
index" ) ) AND ( ( PUBYEAR > 1999 AND PUBYEAR < 2018 ) ) AND ( LIM
IT-TO ( SRCTYPE , "j " ) ) AND ( LIMIT-TO ( DOCTYPE , "ar " ) OR LIMIT-
TO ( DOCTYPE , " re " ) ) AND ( LIMIT-TO ( DOCTYPE , "ar" ) OR LIMIT-
TO ( DOCTYPE , "re" ) )
Cochrane ("conjugated linoleic acid" OR "conjugated fatty acid" OR "rumenic acid" OR 125
"CLA") AND ("weight" OR "obese" OR “obesity” OR "body composition" OR
"adiposity" OR "slim" OR "waist" OR "abdomen" OR "BMI" OR "body mass
index") AND ([2000-2017]/py)