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The effect of berberine supplementation on obesity parameters, inflammation

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The effect of berberine supplementation on obesity parameters, inflammation and

liver function enzymes: A systematic review and meta-analysis of randomized
controlled trials

Omid Asbaghi, Niloofar Ghanbari, Mahdi shekari, Zeljko Reiner, Elaheh Amirani,
Jamal Hallajzadeh, Liaosadat Mirsafaei, Zatollah Asemi
PII: S2405-4577(20)30080-2
DOI: https://doi.org/10.1016/j.clnesp.2020.04.010
Reference: CLNESP 634

To appear in: Clinical Nutrition ESPEN

Received Date: 24 January 2020

Revised Date: 31 March 2020
Accepted Date: 20 April 2020

Please cite this article as: Asbaghi O, Ghanbari N, shekari M, Reiner Z, Amirani E, Hallajzadeh J,
Mirsafaei L, Asemi Z, The effect of berberine supplementation on obesity parameters, inflammation and
liver function enzymes: A systematic review and meta-analysis of randomized controlled trials, Clinical
Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.04.010.

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1 The effect of berberine supplementation on obesity parameters, inflammation

2 and liver function enzymes: A systematic review and meta-analysis of

3 randomized controlled trials

5 Omid Asbaghi1, Niloofar Ghanbari1, Mahdi shekari3, Željko Reiner2, Elaheh Amirani4, Jamal

6 Hallajzadeh5†, Liaosadat Mirsafaei6, Zatollah Asemi*4

1
7 Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran
2
8 Department of Internal Medicine, University Hospital Centre Zagreb, School of Medicine,

9 University of Zagreb, Zagreb, Croatia

3
10 Departments of Nutrition, Faculty of Health, Qazvin University of Medical Sciences Qazvin, Iran
4
11 Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of

12 Medical Sciences, Kashan, I.R. Iran

5
13 Department of Biochemistry and Nutrition, Research Center for Evidence-Based Health

14 Management, Maragheh University of Medical Science, Maragheh, Iran

6
15 Department of Cardiology, Ramsar Campus, Mazandaran University of Medical Sciences,

16 Sari, Iran

17 Running Title: Berberine and anthropometric indices

18 * Corresponding Author. Zatollah Asemi, PhD. Tel: +98-31-55463378; Fax: +98-31-55463377.

19 E-mail addresses: asemi_r@yahoo.com (Z.Asemi).

20 † Co-correspondence: Jamal Hallajzadeh, PhD. Research Center for Evidence-Based Health

21 Management, Maragheh University of Medical Science, Maragheh, Iran, E-mail addresses:

22 jamal.hallaj@yahoo.com.

23

1
24 Abstract

25 Introduction: So far, no study has summarized the findings on the effects of berberine intake on

26 anthropometric parameters, C-reactive protein (CRP) and liver enzymes. This systematic review

27 and meta-analysis were done based upon randomized controlled trials (RCTs) to analyze the

28 effects of berberine on anthropometric parameters, CRP and liver enzymes.

29 Method: Following databases were searched for eligible studies published from inception to 30

30 July 2019: MEDLINE, EMBASE, Web of Science, PubMed and Google scholar. Necessary data

31 were extracted. Data were pooled by the inverse variance method and expressed as mean

32 difference with 95% Confidence Intervals (95% CI).

33 Result: 12 studies were included. Berberine treatment moderately but significantly decreased

34 body weight (WMD=-2.07 kg, 95% CI -3.09, -1.05, P<0.001), body mass index (BMI) (WMD=-

35 0.47 kg/m2, 95% CI -0.70, -0.23, P<0.001), waist circumference (WC) (WMD=-1.08 cm, 95%

36 CI -1.97, -0.19, P=0.018) and C-reactive protein (CRP) concentrations (WMD=-0.42 mg/L, 95%

37 CI -0.82, -0.03, P=0.034). However, berberine intake did not affect liver enzymes, including

38 alanine aminotransferase (ALT) (WMD=-1.66 I/U, 95% CI -3.98, 0.65, P=0.160) and aspartate

39 aminotransferase (AST) (WMD=-0.87 I/U, 95% CI -2.56, 0.82, P=0.311).

40 Conclusion: This meta-analysis found a significant reduction of body weight, BMI, WC and

41 CRP levels associated with berberine intake which may have played an indirect role in improved

42 clinical symptoms in diseases with metabolic disorders. Berberine administration had no

43 significant effect on ALT and AST levels.

44 Keywords: Berberine, body weight, body mass index, C-reactive protein, liver enzymes, meta-

45 analysis

46

2
47 Practical applications

48 This meta-analysis demonstrated that berberine supplementation significantly reduced decrease

49 body weight, BMI, waist circumference and C-reactive protein plasma levels, but did not affect

50 ALT and AST levels. Therefore, berberine supplementation may have played an indirect role in

51 improved clinical symptoms in diseases with metabolic disorders due to its effect on

52 anthropometric indices and C-reactive protein plasma levels.

53

3
54 1. Introduction

55 Increased body weight is associated with different diseases, particularly cardiovascular diseases

56 (CVD), type 2 diabetes mellitus (T2DM), obstructive sleep apnea, some types of cancer,

57 osteoarthritis and depression [1]. In addition, nonalcoholic fatty liver disease (NAFLD) and

58 elevated liver enzymes are closely linked to several metabolic syndrome features [2, 3]. Recent

59 research proved that populations with elevated basal concentrations of C-reactive protein (CRP)

60 are at an increased risk of CVD, diabetes and hypertension [4, 5]. There is a rising trend to use

61 traditional medicinal plants, particularly in some parts of the world, because they are often

62 cheaper and more available or because patients are reluctant to take drugs and they believe that

63 plants are “more natural” [6, 7]. There are some phytochemicals (or nutraceuticals), including

64 capsaicin, resveratrol, curcumin, green tea epigallocatechin gallate (EGCG) and berberine, that

65 have effects on thermogenic activation based upon different modes of action [8]. Berberis

66 vulgaris (B. vulgaris) is used as pharmaceutical more than 2,500 years [9].

67

68 Different parts of this plant have specific therapeutic effects. Berberine, an isoquinoline alkaloid,

69 is the major active part of B. vulgaris [10]. A meta-analysis by Wei et al.[11] indicated that in

70 patients with NAFLD, berberine intake was associated with an improvement in glycemic control,

71 serum lipoproteins and liver function. Several randomized clinical trials (RCTs) have indicated a

72 beneficial effect of berberine on anthropometric parameters and biomarkers of inflammation as

73 well as on liver function in different conditions [12, 13]. However, some other studies could not

74 confirm such effects [14, 15].

75

4
76 There is evidence suggesting that the activation of AMP-activated protein kinase (AMPK)

77 signaling pathway, which is a key regulator of energy metabolism and controls inflammatory

78 processes, can be affected by berberine [16, 17]. Berberine can also downregulate the expression

79 of pro-inflammatory genes and those involved in adipocyte differentiation like PPAR-γ [18].

80 Despite these studies, no earlier meta-analysis has summarized findings on the effects of

81 berberine on anthropometric parameters, CRP and liver enzymes. Therefore, this meta-analysis

82 was performed to summarize all the existing RCTs evidence and to evaluate the effects of

83 berberine on anthropometric parameters, CRP and liver enzymes.

84

85 2. Methods

86 2.1. Search and studies selection strategies

87 Eligible RCTs were identified using Cochrane Library, Embase, Medline, Web of Science,

88 PubMed and Google scholar databases for relevant articles published from inception until 30

89 July 2019, and by manually searching the reference list of the located articles. Studies that

90 evaluated the of berberine intake on anthropometric parameters, CRP and liver enzymes were

91 found by using the following MeSH and text words: intervention ["berberine" OR "huangliansu"

92 OR "berberinum" OR "Xiaopojian"], and outcomes "body weight" OR "body mass index (BMI)"

93 OR "waist circumference (WC)" OR "inflammation" OR "C-reactive protein (CRP)" OR

94 "alanine aminotransferase (ALT)" OR "aspartate aminotransferase (AST)". Additional manual

95 searches including reference lists of related and studies previously published reviews were

96 reviewed to increase sensitivity of search strategy. Studies included in this meta-analysis had to

97 fulfill the following criteria: 1) original trials, 2) human trials, 3) written in English and 4) the

98 trials which reported mean changes or mean difference of anthropometric parameters, CRP and

5
 99 liver enzymes with standard deviation (SD) for the intervention and control groups. Other studies

100 such as in vitro studies, animal experiments, case reports, trials without a control group,

101 observational studies and studies that did not achieve the least quality score were excluded from

102 this meta-analysis.

103

104 2.2. Data extraction and quality assessment

105 Two authors (OA and EA) independently extracted the data and assessed its quality using

106 standard forms and the Cochrane Collaboration risk of bias tool [19, 20], respectively. This tool

107 is based on information on the following domains: randomization generation, allocation

108 concealment, blinding of subjects and outcome assessment, incomplete outcome data, and

109 selective outcome reporting, and other sources of bias. When there was disagreement among

110 them, it was resolved by third author (ZA). From eligible studies the following data were taken:

111 1) first authors’ name 2) publication year 3) age, sex, and body composition and/or metabolic

112 parameters of study participants 4) study location 5) number of subjects in intervention and

113 control groups 6) study design 7) duration of the intervention in each intervention group.

114

115 2.3. Data analysis

116 The effects of berberine intake on the changes of the following parameters were calculated: 1)

117 anthropometric parameters, 2) CRP and 3) liver enzymes. Weighted mean difference (WMD)

118 with 95% CI was used for pooling data to determine the effect sizes. The change score approach

119 was used to calculate the effect size of berberine consumption on the analyzed parameters. The

120 random-effect model was used to report the pooled effect sizes using 95% CI. To calculate the

121 SD changes, the following formula was used: SD = square root [(SD pre-treatment)2 (SD

6
122 posttreatment)2 - (2R × SD pre-treatment × SD post-treatment)], correlation coefficient (R-

123 value) was considered 0.9 [21]. When an SEM or SE was reported instead of SD, the SD was

124 calculated based on the following formula: SD= SEM × √n (n = sample size in each group).

125 Heterogeneity of included studies was assessed using Cochrane’s Q test (with significant P-value

126 <0.1) and I-square test (I2 greater than 50 percent showing significant heterogeneity). The funnel

127 plot was used to determine the publication bias. STATA 11.0 (Stata Corp., College Station, TX)

128 was applied for data analysis.

129

130 3. Results

131 3.1. Study selection

132 After initial search in databases, 2315 articles were found. 1025 articles were duplicates and

133 removed. 1290 articles were screened based on their title and abstract. 1270 publications were

134 excluded because they were animal studies, reviews or were unrelated with the topic which was

135 analyzed. 20 articles were eligible to be analyzed based on the full-text. 8 studies were omitted

136 because the desired data were lacking. Finally, 12 studies were included in this systematic review

137 and meta-analysis. The summary of selected studies is shown in Fig.1.

138

139 3.2. Characteristics of included studies

140 The main characteristics of the eligible studies are presented in Table 1. Our analysis included

141 data from 1015 volunteers, 508 in the berberine arm and 507 in the control arm. Eligible studies

142 were published between 2005 and 2018. The studies were performed in China, Italy, Mexico and

143 Iran. All studies were designed as parallel studies. The trials used different doses of berberine

144 (ranging from 300 mg/day to 1500 mg/day) and trials duration was between 1 month and 24

7
145 months. Subjects enrolled in the eligible trials had allograft renal transplant surgery, T2DM,

146 polycystic ovary syndrome (PCOS), acute coronary syndrome, low cardiovascular risk,

147 metabolic syndrome, NAFLD and acute ischemic stroke. Subjects enrolled in 4 studies had

148 normal body weight and others were overweight or obese. The quality assessment of studies is

149 shown in Table 2.

150

151 3.3. Effect of berberine treatment on anthropometric parameters, CRP and liver enzymes

152 The effect of berberine intake on body weight, BMI, WC, CRP, ALT and AST was assessed in 5,

153 8, 5, 4, 4, and 3 studies, respectively. Berberine treatment significantly decreased anthropometric

154 including body weight (WMD=-2.07 kg, 95% CI -3.09, -1.05, P<0.001; Fig. 2.A), BMI

155 (WMD=-0.47 kg/m2, 95% CI -0.70, -0.23, P<0.001; Fig. 2.B) and WC (WMD=-1.08 cm, 95%

156 CI -1.97, -0.19, P=0.018; Fig. 2.C) as well as CRP concentrations (WMD=-0.42 mg/L, 95% CI -

157 0.82, -0.03, P=0.034; Fig.2.D). However, berberine intake did not affect liver enzymes, including

158 ALT (WMD=-1.66 I/U, 95% CI -3.98, 0.65, P=0.160; Fig. 2.E) and AST (WMD=-0.87 I/U,

159 95% CI -2.56, 0.82, P=0.311; Fig. 2.F). It has to be stressed that there was significant

160 heterogeneity for CRP (I2=76.4 and P=0.005); so we used random-model for pooling effect sizes.

161 On the other hand, we used the fixed-model for all the other factors (Fig.2. A-F).

162

163 4. Discussion

164 In this meta-analysis of RCTs, we evaluated the effects of berberine on anthropometric

165 parameters, CRP and liver enzymes. This meta-analysis demonstrated that berberine intake was

166 associated with improved anthropometric parameters such as body weight, BMI and WC as well

167 as CRP values, but did not change the plasma levels of liver enzymes.

8
168

169 4.1. Effects on obesity

170 Obesity is an important component of metabolic syndrome (MetS) and considered as an

171 important risk factor for different diseases [22]. Increased inflammatory markers and metabolic

172 profiles increase the risk of CVD and diabetes [4, 5, 23, 24]. This meta-analysis demonstrated

173 that berberine reduced body weight, BMI and WC. Some trials have reported that berberine

174 consumption had beneficial effects on anthropometric mesurments. For example, Yan et al.[12]

175 reported that 500 mg of berberine consumption during four months decreased body weight, BMI

176 and WC in NAFLD patients. Zhang et al.[25] also showed that three months of berberine

177 consumption at a dosage of 500 mg twice per day decreased body weight and BMI in T2DM

178 patients with dyslipidemia. Another study proved that in women with PCOS berberine intake

179 during 3 months decreased WC and WHR but without weight and BMI changes [26]. However,

180 a meta-analysis of animal models of cancer indicated that berberine intake did not affect body

181 weight [27]. Obesity can cause insulin resistance and impaired glucose metabolism which are all

182 components of MetS [28]. Obesity-induced inflammation can exacerbate insulin resistance [29]

183 and it has been shown that berberine has anti-inflammatory effects [30]. Most recently it has

184 been shown that berberine can promote the recruitment and activation of brown adipocyte

185 differentiation and thermogenesis epigenetically through AMPK–PRDM16 axis, contributing to

186 elevated systemic energy expenditure and therefore it might have antiadipose effects [31].

187

188 It has been shown without any doubt that overweight, obesity and higher WC are associated with

189 increased mortality [32, 33]. Obesity is not only an important risk factor for cardiovascular

190 diseases and T2DM but also risk factor for different types of cancer [34]. Therefore, weight

9
191 management has many favorable effects. Weight reduction decreases the risk of developing

192 diabetes [35, 36]. In obese subject and patients with essential hypertension, weight reduction is

193 associated with a decrease in blood pressure [37, 38]. It has been demonstrated that modest

194 weight loss improves pulse wave velocity which is a marker of arterial stiffness [39]. Berberine

195 most probably achieves anti-obesity effects by modulating the expression of transcription factors

196 and genes involved in the adipogenesis such as cAMP-response element-binding (CREB) protein

197 [40], GATA-2 and GATA-3 [41], and PPAR-γ [42] which are associated with the inhibition of

198 adipocyte differentiation. Berberine also enhances the expression of uncoupling protein 1

199 (UCP1) and other thermogenic genes in white and brown adipose tissue and primary adipocytes

200 by a pathway involving AMPK and PPAR-γ coactivator-1 alpha [43]. Moreover, evidence from

201 animal studies indicated that berberine modifies gut microbiota, which decrease insulin

202 resistance, and inflammation and finally improve body weight [44].

203

204 4.2. Effects on liver function and CRP

205 In this meta-analysis, we found that berberine intake decreased CRP, while ALT and AST levels

206 remained unchanged. Overall, pooling information from all qualified RCTs, provides more

207 precise and powerful evidence than those from the individual studies. However, these studies are

208 heterogeneous with respect to study duration, sampling method, age ranges, dosage of berberine

209 used, the characteristics of participants, differences between intervention and control groups,

210 cross-over design or parallel design, allocation concealment, and dietary intake of participants. In

211 particular, the wide variation in the amount and formulation of berberine may be the most

212 important contributor to the heterogeneity seen in our results. In a study by Meng et al.[30], 600

213 mg/day of berberine did not have any effect on AST or ALT. Although our meta-analysis

10
214 indicated that berberine had no significant effect on liver enzymes, some animal studies

215 suggested that berberine treatment might have some hepatoprotective effects by suppression of

216 oxidative stress, inflammatory responses and hepatocyte necrosis [45, 46]. A study by Dai et

217 al.[47] indicated that the consumption of 300 mg/day of berberine with a two-week no-treatment

218 interval every five months decreased CRP levels in patients with T2DM during 24 months. A

219 previous meta-analysis by Wei et al.[11] suggested that berberine can improve liver function in

220 NAFLD patients. Nevertheless, in two studies on T2DM patients with dyslipidemia [25] and

221 patients with ACS [48], berberine did not improve CRP levels. Inflammation is associated with

222 the pathogenesis of atherosclerosis [49]. There is evidence that elevated CRP is associated with a

223 number of diseases including hypertension, CVD, T2DM and its complications, as well as some

224 other diseases such as Alzheimer and Parkinson disease [50]. In general population, increased

225 CRP levels can independently predict the risk of all-cause and cardiovascular mortality [51].

226 Several mechanisms have been proposed for the anti-inflammatory effects of berberine,

227 including modulation of gut microbiota and intestinal permeability [52], decreased expression of

228 nuclear factor-kappa B (NF-κB) [53], and activation of AMPK/mTOR signaling pathway [54] as

229 well as some other possible mechanisms [55].

230

231 The present meta-analysis is among rare studies that summarize findings from earlier studies on

232 anthropometric parameters, CRP and liver enzymes. Therefore it is important to consider some

233 imitations of this meta-analysis when interpreting the results and producing conclusions. This

234 meta-analysis had few limitations. One of the most important was that subjects in the included

235 studies had different diseases, including diabetes, non-alcoholic fatty liver disease, PCOS and

236 CVD which might have an influence on the results. Moreover, due to the heterogeneity between

11
237 studies, evident from the variations in duration of berberine intake, the dosage and frequency of

238 berberine used, results should be interpreted with caution. The number of studies and sample size

239 of participant's study that finally entered to the current meta-analysis was low. This meta-

240 analysis cannot support the beneficial effects of berberine supplementation on body weight,

241 BMI, WC and CRP levels due to low number of studies and high heterogeneity in the included

242 studies.

243

244 5. Conclusions

245 This meta-analysis found a significant reduction of body weight, BMI, WC and CRP levels

246 associated with berberine intake. Berberine administration had no significant effect on ALT and

247 AST levels. Therefore, berberine intake may have played an indirect role in improved clinical

248 symptoms in diseases with metabolic disorders due to its effect on body weight, BMI, WC and

249 CRP levels.

12
Funding

Not applicable.

Author contribution

OA and ZA contributed in conception, data collection and manuscript drafting. NG, MS, ZR,

EA, JH and LM contributed in conception, data collection and manuscript drafting. All authors

read and approved the final version of the paper.

Conflicts of interest

All the authors declared that they have no conflicts of interest.

13
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19
Identification

Records identified through database searching: Pubmed (358),

Scopus (931), Embase (548), ISI Web of science (478)
(n=2315)

Duplicates removed
(n=1025)
Screening

Records screened
(n=1290)
Records excluded
(n=1270)
1. Animal studies (n=265)
2. Reviews (n=137)
Not related studies
Full-text articles assessed
Eligibility

for eligibility
(n=20)

Not having the desired

data (n=8)

Studies included in
qualitative synthesis
(n=12)
Included

Studies included in
quantitative synthesis (meta-
analysis)
(n=12)

Fig.1. Flowchart of the study selection for inclusion in the systematic reviews and meta-analyses

20
Table 1. Characteristics of included primary clinical trials
Author Year Country Study Participants Sex Mean age Mean BMI Trial Sample size Outcomes
design (intervention/ (intervention/ duration Treatment Control
group group (intervention/control)
control) control) (months)
Wu et al. [56] 2005 China Parallel Allograft F/M 42.5/39.6 20.5/20.4 3 600 mg Nothing 52/52 ALT
renal berberine
transplant
operation
Zhang et al. [25] 2008 China Parallel T2DM and F/M 51/51 25.2/25.9 3 1,000 mg Placebo 58/52 BW, BMI, CRP
dyslipidemia berberine
Gu et al. [14] 2010 China Parallel T2DM and F/M 51/50 25.1/26.2 3 1,000 mg Placebo 30/30 BW, BMI
dyslipidemia berberine
Wei et al. [26] 2012 China Parallel PCOS F 25.7/26.7 25.6/24.9 3 1,500 mg Placebo + 31/28 BW, BMI, WC
berberine + compound
compound cyproterone
cyproterone acetate
acetate
Meng et al. [48] 2012 China Parallel Acute F/M 63.1/63.3 24.1/23.5 1 300 mg Nothing 61/69 CRP
coronary berberine
syndrome
Derosa et al. [57] 2013 Italy Parallel Low F/M 53/54 25.6/25.5 3 1,000 mg Placebo 68/69 BW, BMI, WC, ALT,
cardiovascular berberine AST
risk
Pérez-Rubio et al. [58] 2013 Mexico Parallel Metabolic F/M 36.9/38.1 36.1/34.2 3 1,500 mg Placebo 12/12 F/M BMI, WC
syndrome berberine 7/7 F
5/5 M
An et al. [59] 2013 China Parallel PCOS F 28.2/28.4 24.6/24.2 3 1,500 mg Placebo 44/43 BMI, WC
berberine
Yan et al. [12] 2015 China Parallel NAFLD F/M 50.7/50.6 28.1/27.3 4 1,500 mg Lifestyle 55/53 BW, BMI, ALT, AST
berberine + intervention
lifestyle
intervention
Dai et al. [47] 2015 China Parallel T2DM F/M 55.3/53.1 24.5/24.1 24 300 mg Nothing 39/33 CRP
berberine
Zhu et al. [60] 2015 China Parallel Acute F/M 63.3/66.3 NR 3 1,200 mg 20 mg 16/28 CRP
ischemic berberine + atorvastatin
stroke 20 mg
atorvastatin
Rashidi et al. [15] 2018 Iran Parallel T2DM F/M 50.2/45.2 29.8/29.1 1 1,000 mg Placebo 40/41 BMI, ALT, AST
berberine

21
Table 2. Quality assessment of included studies

Random Selective Blinding of Blinding of

Allocation Other sources Incomplete
Study (year) Sequence outcome participants outcome
concealment of bias outcome data
Generation reporting personnel assessors
Wu et al. [56] U H H H H H H
Zhang et al. [25] L U L U L U L
Gu et al. [14] U H H H L U L
Wei et al. [26] L U L U H L L
Meng et al. [48] U U L H L L L
Derosa et al. [57] L U L L L U L
Pérez-Rubio et al.[58] L U H H L U L
An et al. [59] L U L H L U L
Yan et al.[12] L L L L H H L
Dai et al.[47] U U L H H H H
Zhu et al.[60] U U L H H H L
Rashidi et al.[15] L U L U L U L
L is low risk of bias; H is high risk of bias; U is unclear risk of bias.

22
Study %

ID WMD (95% CI) Weight

Zhang et al. 2008 -1.00 (-20.60, 18.60) 0.27

Gu et al. 2010 -0.20 (-25.33, 24.93) 0.16

Wei et al. 2012 -0.08 (-4.16, 4.00) 6.22

Derosa et al. 2013 0.60 (-5.37, 6.57) 2.90

Yan et al. 2015 -2.30 (-3.37, -1.23) 90.45

Overall (I-squared = 0.0%, p = 0.755) -2.07 (-3.09, -1.05) 100.00

-25.3 0 25.3

Fig.2A: Effect of berberine on body weight

Study %

ID WMD (95% CI) Weight

Zhang et al. 2008 -0.40 (-2.26, 1.46) 1.58

Gu et al. 2010 -0.20 (-2.43, 2.03) 1.10

Wei et al. 2012 -0.03 (-0.53, 0.47) 22.03

Derosa et al. 2013 -0.40 (-0.79, -0.01) 35.99

Pérez-Rubio et al. 2013 (Both sexes) -0.50 (-4.08, 3.08) 0.43

An et al. 2013 -0.90 (-2.44, 0.64) 2.31

Yan et al. 2015 -0.79 (-1.18, -0.40) 36.15

Rashidi et al. 2018 0.14 (-3.53, 3.81) 0.41

Overall (I-squared = 0.0%, p = 0.517) -0.47 (-0.70, -0.23) 100.00

-4.08 0 4.08

Fig.2B: Effect of berberine on BMI

Study %

ID WMD (95% CI) Weight

Wei et al. 2012 -3.68 (-10.45, 3.09) 1.73

Derosa et al. 2013 0.00 (-1.14, 1.14) 60.74

Pérez-Rubio et al. 2013 (Female) -2.00 (-24.49, 20.49) 0.16

Pérez-Rubio et al. 2013 (Male) -1.00 (-36.10, 34.10) 0.06

An et al. 2013 -2.90 (-11.39, 5.59) 1.10

Yan et al. 2015 -2.70 (-4.18, -1.22) 36.21

Overall (I-squared = 43.1%, p = 0.118) -1.08 (-1.97, -0.19) 100.00

-36.1 0 36.1

Fig.2C: Effect of berberine on waist circumference

Study %

ID WMD (95% CI) Weight

Zhang et al. 2008 -1.14 (-6.25, 3.97) 0.58

Meng et al. 2012 -0.18 (-0.42, 0.06) 45.13

Dai et al. 2015 -0.62 (-0.65, -0.59) 54.19

Fei-qi et al. 2015 -0.47 (-13.04, 12.10) 0.10

Overall (I-squared = 76.4%, p = 0.005) -0.42 (-0.82, -0.03) 100.00

NOTE: Weights are from random effects analysis

-13 0 13

Fig.2D: Effect of berberine on CRP

Study %

ID WMD (95% CI) Weight

Wu et al. 2005 -4.70 (-116.20, 106.80) 0.04

Derosa et al. 2013 2.00 (-9.65, 13.65) 3.95

Yan et al. 2015 -6.90 (-12.46, -1.34) 17.33

Rashidi et al. 2018 -0.69 (-3.30, 1.92) 78.68

Overall (I-squared = 30.5%, p = 0.229) -1.66 (-3.98, 0.65) 100.00

-116 0 116

Fig.2E: Effect of berberine on ALT

View publication stats

Study %

ID WMD (95% CI) Weight

Derosa et al. 2013 2.00 (-11.51, 15.51) 1.56

Yan et al. 2015 -2.40 (-5.46, 0.66) 30.56

Rashidi et al. 2018 -0.25 (-2.30, 1.80) 67.88

Overall (I-squared = 0.0%, p = 0.476) -0.87 (-2.56, 0.82) 100.00

-15.5 0 15.5

Fig.2F: Effect of berberine on AST

Fig.2A-F. Meta-analysis metabolic profiles and anthropometric measurements weighted mean difference estimates
for A) Body weight, B) BMI, C) Waist circumference, D) C-reactive proteine, E) ALT, F) AST in the berberine and
placebo groups (CI=95%).