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Received: 19 September 2021
|
Revised: 7 January 2022
|
Accepted: 2 March 2022
DOI: 10.1002/jbt.23038
REVIEW
Antioxidant for treatment of diabetic complications:
A meta‐analysis and systematic review
Ou Zhong
1
|Jialin Hu
1
|Jinyuan Wang
1
|Yongpeng Tan
1
|Linlin Hu
2
|
Xiaocan Lei
1
1
Clinical Anatomy & Reproductive Medicine
Application Institute, Hengyang Medical
School, University of South China, Hengyang,
Hunan, China
2
Reproductive Medicine Center, The Affiliated
Hospital of Youjiang Medical University for
Nationalities, Baise, China
Correspondence
Xiaocan Lei, Clinical Anatomy & Reproductive
Medicine Application Institute, Hengyang
Medical School, University of South China,
Hengyang, Hunan, 421001, China.
Email: 2019000013@usc.edu.cn
Linlin Hu,Reproductive Medicine Center, The
Affiliated Hospital of Youjiang Medical
University for Nationalities, Baise 533000,
China.
Email: hutwolin@126.com.
Funding information
Key Lab for Clinical Anatomy & Reproductive
Medicine of Hengyang City,
Grant/Award Number: 2017KJ182; Natural
Science Foundation of Hunan Province,
Grant/Award Number: 2020JJ5500; National
Natural Science Fund of China,
Grant/Award Number: 82101720; Natural
Science Foundation of Guangxi in China,
Grant/Award Number:
2021GXNSFBA220010
Abstract
Antioxidants may provide a complementary treatment for patients with chronic
diseases. Nevertheless, studies that have measured the effects of antioxidant on
diabetes complications have provided conflicting results. This study aimed to elucidate
the association between antioxidant and diabetic complications and to develop robust
evidence for clinical decisions by systematic reviews and meta‐analysis. PubMed,
Embase, The Cochrane Library, Web of Science, Scopus databases were searched to
collect clinical studies related to the efficacy of antioxidants in the treatment of diabetes
complications from inception to May 5, 2021. Statistical meta‐analyses were performed
using the RevMan 5.4 software. Stata16 software was used to detect publication bias.
The data of diabetic nephropathy (DN), diabetic nonalcoholic fatty liver disease
(NAFLD), and diabetic periodontitis were collected to analyze the effect of antioxidant
on diabetes and the above three complications. The meta‐analysis results showed that
antioxidant treatment was associated with significantly changes in the fasting plasma
glucose (FPG) (standardized mean difference [SMD]: −0.21 [95% confidence interval
[CI]: −0.33, −0.10], p< 0.001), hemoglobin A1c (HbA1c) (MD: −0.41 [95% CI: −0.63,
−0.18], p< 0.001), total antioxidant capacity (TAC) (SMD: 0.44 [95% CI: 0.24, 0.63],
p< 0.001) and malondialdehyde (MDA) (SMD: −0.82 [95% CI: −1.24, −0.41], p< 0.001)
than the control group. Antioxidant supplements have the potential to treat three
complications of diabetes. In conclusion, the meta‐analysis results indicate that
antioxidant treatment is effective clinically for diabetes mellitus and its complications.
KEYWORDS
diabetes complications, diabetic nephropathy, meta‐analysis, nonalcoholic fatty liver disease,
periodontitis
1|INTRODUCTION
Diabetes mellitus (DM) is a major global health crisis of the 21st
century. According to the Global Diabetes Map released by the
International Diabetes Federation (IDF) in 2019, the number of
people affected by diabetes quadrupled from 108 million people
in 1980 to a staggering figure of 463 million people worldwide in
2019,
[1]
and this number is expected to continue to rise in the
future. It is now established that diabetes can adversely affect
variousorgansofthebody,suchasnerves,liver,kidneys,
periodontal and cardiovascular systems, resulting in the develop-
ment of neuropathy, diabetic nephropathy, nonalcoholic fatty
J Biochem Mol Toxicol. 2022;e23038. wileyonlinelibrary.com/journal/jbt © 2022 Wiley Periodicals LLC
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https://doi.org/10.1002/jbt.23038
Ou Zhong and Jialin Hu equally contributed to this work.
liver disease, and periodontitis.
[2–4]
Studies have shown that
various complications in patients with diabetes may be related to
increased oxidative stress.
[5]
Sustained hyperglycemia causes
excessive production of reactive oxygen species (ROS) by
enhancing mitochondrial oxygen consumption and damaging
mitochondrial function, leading to the imbalance between ROS
and antioxidants, thus leading to oxidative stress. Under
physiological conditions, cells are maintained in a reducing
environment provided by endogenous antioxidants or antioxidant
enzymes. Increased levels of oxidative stress can lead to lipid
peroxidation, cell DNA damage, and other consequences, which
ultimately lead to the deterioration of mitochondrial function and
cell death.
[6,7]
Antioxidants can reduce oxidative stress and
improve diabetes and its complications by inhibiting the forma-
tion of free radicals.
[8]
In clinical studies, antioxidant treatments such as vitamins C
and E and α‐lipoic acid provided positive results to show that they
can prevent or stop only early surrogate markers of diabetes
complications.
[9]
However, larger studies, such as the Heart
Outcomes Prevention Study using a dose of 400 IU/day of
vitamin E, d‐α‐tocopherol, did not show improvement of micro-
vascular or cardiovascular damage in greater than 3000 indivi-
duals who have had diabetes for several years.
[10]
Smaller
studies using a dose of 600 mg/day or higher of vitamin E
suggest that vitamin E may improve cardiovascular function.
[11]
However, most large studies using vitamin E alone or in
combination with other antioxidants have not yielded positive
benefits for decreasing the development or progression of
diabetic microvascular and cardiovascular pathologies or mortal-
ity.
[12]
Meta‐analysis of data from 11 included randomized
controlled trials (RCTs) did not support convincing evidence as
to a significant increasing effect of pomegranate intake in total
antioxidant capacity (TAC) and paraxonase as well as not
significant decrease in malondialdehyde (MDA).
[13]
To our best
knowledge, no systematic review has been performed to explore
if antioxidant treatments have beneficial effects on the diabetes
complications.
Thus, we aimed to conduct a systematic review to gather current
evidence on the effects of antioxidant on diabetes complications of
diabetic nephropathy, nonalcoholic fatty liver disease, and periodon-
titis, to elucidate its real benefits.
2|MATERIALS AND METHODS
2.1 |Search strategy
PubMed, Embase, The CENTRAL, Web of Science, and Scopus
databases were searched to collect clinical studies related to the
efficacy of antioxidants in the treatment of diabetes complications
from inception to May 5, 2021. Search is conducted by combining
subject and free words. See Supporting Information Appendix 1 for
detailed query words.
2.2 |Inclusion and exclusion criteria
Inclusion criteria: (1) All patients had diabetes and combined with
nephropathy or nonalcoholic fatty liver disease or periodontitis. We
defined diabetic kidney disease as diabetic people with (a) a
proteinuria level greater than 0.3 g/24 h or (b) microalbuminuria
(urinary albumin‐to‐creatinine ratio [UACR] > 10 mg/mmol) or (c)
reduced estimated glomerular filtration rate (eGFR) (<110 ml/min/
1.73 m
2
); defined diabetic periodontitis as diabetic people with mild
and moderate periodontitis (pocket depth [PD] ≥4 mm and clinical
attachment loss [CAL] ≥1 mm); defined diabetic nonalcoholic fatty
liver disease as diabetic people with histologically confirmed NAFLD
or sonographic findings compatible with fatty liver. Control group:
healthy people without diabetes (see Supporting Information
Appendix 1 for detailed criteria); (2) Intervention: The treatment
group received antioxidant and the control group received placebo.
Due to the limited sample size of the NAFLD group, one nonplacebo
control sample was included. (3) Literature published in English.
Exclusion criteria: (1) Case‐series/reports, expert opinions, basic
science, conference abstracts and review articles; (2) Animal
experiments, cell experiments, and other literatures without available
data; (3) Literatures with poor quality and obvious statistical errors;
(4) Without the outcome indicators we need.
2.3 |Literature screening, data extraction
One investigator generated the search strategies and retrieved
literature. Two investigators independently reviewed the studies
and determined whether they met prespecified criteria, in addition to
verifying the extracted data with complete agreement. If there is any
dispute, the third party shall confirm and decide whether to include it
or not.
Through the previous process, we collected and analyzed the
data of 15 indicators and described the statistical model of each
indicator in Table 1. Including glucose metabolism‐related indicators
fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c); systemic
oxidation reaction state‐related indicators TAC and MDA; renal
function‐related indicators eGFR, blood urea nitrogen (BUN), Serum
creatinine, Cockcroft‐Gault formula to estimate of creatinine clear-
ance (CG) and UACR; liver function‐related indicators aspartate
aminotransferase (AST), alanine aminotransferase (ALT), low‐density
lipoprotein (LDL) and high‐density lipoprotein (HDL); periodontal
state indicators PD and CAL.
2.4 |Statistical analysis
Statistical meta‐analyses were performed using the RevMan 5.4 software.
Continuous data were calculated with weighted mean difference (MD)
andconfidenceintervalsweresetat95%,p< 0.05 was considered
statistically significant. Due to different data units, standardized mean
difference (SMD) was used for calculation (see Table 1). If the analysis
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ZHONG ET AL.
result is p>0.1 or I
2
< 50%, indicating that the heterogeneity among the
included studies was small, a fixed‐effect model was used; conversely,
the heterogeneity among the included studies was significant, and the
random‐effectsmodelwasadopted.Stata16softwarewasusedtodetect
publication bias, Egger and Begg methods were mainly used, p>0.05
indicates no significant publication bias (because Egger examination is
more sensitive, when the two results are contradictory, the Egger
examination results are given priority).
3|RESULTS
3.1 |Study selection
We identified 12,858 articles in the initial retrieval, including PubMed
(n= 581), Embase (n= 222), The Cochrane library (n= 6949), Web of
Science (n = 4031), and Scopus (n= 1068). Of these, 2326 duplicate
articles were excluded after carefully examining the titles and
abstracts. After layer‐by‐layer screening, 36 studies were included
in the meta‐analysis, the literature screening process and results are
shown in Figure 1.
3.2 |Study characteristics
Thirty‐six studies were eventually included in this study. The quality
of the included articles was evaluated using the bias risk assessment
tool for RCT in Cochrane Systematic Review Manual 5.1.0, and all the
included studies reached a medium to high level (Figure 2). However,
TABLE 1 Statistical models of clinical outcomes
Outcomes
Heterogeneity Analysis
model
Summary
statisticI
2
(%) pvalue
FPG (mg/dl) 39 0.03 Fixed SMD
HbA1c (%) 81 <0.001 Random MD
TAC (mmol/L) 48 0.06 Fixed SMD
MDA (μmol/L) 83 <0.001 Random SMD
eGFR (ml/min/1.73 m
2
) 45 0.05 Fixed SMD
BUN (mg/dl) 87 <0.001 Random SMD
Serum creatinine e(mg/dl) 0 0.70 Fixed SMD
CG (ml/min) 0 0.98 Fixed SMD
UACR (mg/mmol) 75 0.0002 Random SMD
AST (IU/L) 81 0.005 Random MD
ALT (IU/L) 84 0.002 Random MD
HDL (mg/dl) 39 0.18 Fixed MD
LDL (mg/dl) 0 0.57 Fixed MD
PD (mm) 92 <0.001 Random MD
CAL (mm) 94 <0.001 Random MD
Abbreviations: AST, aspartate aminotransferase; ALT, alanine
aminotransferase; BUN, blood urea nitrogen; CAL, clinical attachment
loss; CG, Cockcroft‐Gault formula to estimate of creatinine clearance;
eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose;
HbA1c, hemoglobin A1c; HDL, high‐density lipoprotein; LDL, low‐density
lipoprotein; MDA, malondialdehyde; PD, pocket depth; SMD,
standardized mean difference; TAC, total antioxidant capacity; UACR,
urinary albumin‐to‐creatinine ratio.
FIGURE 1 Flowchart of study selection
ZHONG ET AL.
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FIGURE 2 Risk of Bias graph of included trials
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ZHONG ET AL.
TABLE 2 Characteristics of included studies
Study
Country Type
Sample size
(antioxidant/
control)
Population characteristics
(antioxidant/control)
Intervention
Duration of
intervention
Diabetic
nephropathy Antioxidant group Control group
Satari, 2021
[14]
Iran DN
RPC
22/24 Age (years): 66.9 ± 6.9/64.3 ± 7.7
BMI (kg/m
2
): 28.8 ± 5.3/27.8 ± 4.2
Melatonin
10 mg/day
Placebo 12 weeks
Koay, 2021
[15]
Malaysia DN
DM2
RPC
31/28 Age (years): 66 (13)/70 (13)
BMI (kg/m
2
): 28.1 ± 4.4/29.1 ± 5.0
Disease duration (years): 15.3 ± 7.6/
17.9 ± 8.9
Vit E 400 mg/day Placebo 2 months
Sattarinezhad,
2019
[16]
Iran DN
DM2
RPC
30/30 Age (years): 56.8 ± 9.7/55.7 ± 10.8
BMI (kg/m
2
): 28.2 ± 3.8/27.3 ± 4.4
Disease duration (years): 16.1 ± 6.6/
14.4 ± 6.3
Resveratrol 500 mg/
day + losartan
12.5 mg/day
Placebo
500 mg/
day +
losartan
12.5 mg/
day
90 days
Tan, 2019
[17]
Malaysia DN
DM2
RPC
27/27 Age (years): 59 ± 10/62.8 ± 11.6
BMI (kg/m
2
): 29.4 ± 5.4/29.3 ± 4.7
Disease duration (years): 20.7 ± 9.9/
16.2 ± 8.1
Vit E 200 mg/day Placebo 12 weeks
Gholnari,
2018
[18]
Iran DN
DM1&2
RPC
25/25 Age (years): 61.1 ± 11.3/61.6 ± 10.0
BMI (kg/m
2
): 30.4 ± 6.1/31.3 ± 4.8
Disease duration (years): 16.7 ± 1.7/
16.5 ± 2.4
CoQ10 100 mg/day Placebo 12 weeks
Aghadavod,
2018
[19]
Iran DN
DM1&2
RPC
27/27 Age (years): 62.2 ± 9.8/64.5 ± 9.2
BMI (kg/m
2
): 30.9 ± 4.7/31.1 ± 6.1
Disease duration (years): 16.4 ± 2.8/
16.1 ± 3.3
Vit E 800 IU/day Placebo 12 weeks
Taghizadeh,
2017
[20]
Iran DN
DM1&2
RPC
30/30 Age (years): 63.7 ± 10.8/63.1 ± 9.6
BMI (kg/m
2
): 30.9 ± 3.3/31.1 ± 3.9
Disease duration (years): 16.1 ± 3.2/
15.7 ± 2.9
Mulberry extract
300 mg/day
Placebo 12 weeks
Soleimani,
2017
[21]
Iran DN
DM1&2
RPC
30/30 Age (years): 62.9 ± 10.5/62.4 ± 9.6
BMI (kg/m
2
): 30.5 ± 7.3/31.6 ± 4.8
Disease duration (years): 16.0 ± 3.2/
15.5 ± 3.4
Omega‐3 fatty acid
1000 mg/day
Placebo 12 weeks
Khatami,
2016
[22]
Iran DN
DM1&2
RPC
30/30 Age (years): 61.2 ± 10.0/62.2 ± 13.8
BMI (kg/m
2
): 30.3 ± 4.9/30.9 ± 5.8
Disease duration (years): 15.4 ± 3.3/
15.2 ± 3.1
Vit E 1200 IU/day Placebo 12 weeks
Jimenez‐
Osorio,
2016
[23]
Mexico DN
RPC
28/23 Age (years): 55.0 ± 1.6/56.2 ± 1.5
BMI (kg/m
2
): 29.7 ± 1.2/27.9 ± 1.1
Curcumin
320 mg/day
Placebo 8 weeks
Bahmani,
2016
[24,25]
Iran DN
DM1&2
RPC
30/30 Age (years): 63.1 ± 12.6/61.4 ± 9.3
BMI (kg/m
2
): 29.8 ± 5.8/30.4 ± 4.9
Disease duration (years): 16.2 ± 2.5/
15.8 ± 2.8
Se 200 µg/day Placebo 12 weeks
Borges,
2016
[26]
Brazil DN
DM1&2
RPC
21/21 Age (years): 63 (60–65)/59 (49–63)
BMI (kg/m
2
): 30.6 (27.5–34.7)/32.7
(28.6–35.5)
Disease duration (years): 16
(12–20)/19 (13–22)
Green tea
polyphenols
800 mg/day
Placebo 12 weeks
Kuchake,
2013.(1)
[27]
India DN
DM2
RPC
54/54 ‐Vit E 400 mg/day +
Vit C 500 mg/day
Placebo 17 weeks
(Continues)
ZHONG ET AL.
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TABLE 2 (Continued)
Study
Country Type
Sample size
(antioxidant/
control)
Population characteristics
(antioxidant/control)
Intervention
Duration of
intervention
Diabetic
nephropathy Antioxidant group Control group
Kuchake,
2013.(2)
[27]
India DN
DM2
RPC
47/54 ‐Reduced glutathione
50 mg/day
Placebo 17 weeks
Kuchake,
2013.(3)
[27]
India DN
DM2
RPC
61/54 ‐Reduced glutathione
+ Vit (E + C)
Placebo 17 weeks
Lewis,
2012.(1)
[28]
USA DN
DM2
RPC
105/106 Age (years): 63.8 ± 9.1/64.4 ± 9.0
BMI (kg/m
2
): 32.5 ± 5.5/34.1 ± 6.4
Disease duration (years): 16.9 ± 8.1/
18.8 ± 9.0
Pyridorin
150 mg/day
Placebo 52 weeks
Lewis,
2012.(2)
[28]
USA DN
DM2
RPC
106/106 Age (years): 63.6 ± 10.4/64.4 ± 9.0
BMI (kg/m
2
): 34.3 ± 7.3/34.1 ± 6.4
Disease duration (years): 17.1 ± 8.4/
18.8 ± 9.0
Pyridorin
300 mg/day
Placebo 52 weeks
Fallahzadeh,
2012
[29]
Iran DN
DM2
RPC
30/30 Age (years):55.9 ± 8.3/57.6 ± 7.5
BMI (kg/m
2
): 28.6 ± 6/29.2 ± 4.8
Disease duration (years): 12 ± 6.8/
12.4 ± 5.8
Silymarin
420 mg/day
Placebo 3 months
Pergola,
2011.(1)
[30]
USA DN
DM2
RPC
57/57 Age (years): 66.9 ± 9.2/67.7 ± 10.0
BMI (kg/m
2
): 36.3 ± 7.8/34.4 ± 8.0
Disease duration (years):
18.2 ± 10.8/17.1 ± 9.9
Bardoxolone methyl
25 mg/day
Placebo 52 weeks
Pergola,
2011.(2)
[30]
USA DN
DM2
RPC
57/57 Age (years): 66.1 ± 8.7/67.7 ± 10.0
BMI (kg/m
2
): 35.0 ± 7.6/34.4 ± 8.0
Disease duration (years): 17.8 ± 9.8/
17.1 ± 9.9
Bardoxolone methyl
75 mg/day
Placebo 52 weeks
Pergola,
2011.(3)
[30]
USA DN
DM2
RPC
56/57 Age (years): 66.7 ± 9.2/67.7 ± 10.0
BMI (kg/m
2
): 35.8 ± 7.3/34.4 ± 8.0
Disease duration (years): 18.6 ± 9.8/
17.1 ± 9.9
Bardoxolone methyl
150 mg/day
Placebo 52 weeks
Khajehdehi,
2011
[31]
Iran DN
DM2
RPC
20/20 Age (years): 52.9 ± 9.2/52.6 ± 9.7 Turmeric
500 mg/day
Placebo 2 months
House,
2010
[32]
Canada DN
DM1&2
RPC
119/119 Age (years): 60.7 ± 11.6/60.1 ± 10.8
BMI (kg/m
2
): 32.6 ± 6.0/32.4 ± 5.5
Disease duration (median (IQR),
years): 19.0 (17.0)/18.0 (16.0)
Folic acid 2.5 mg/d
ay+ Vit B6
25 mg/day + Vit
B12 1 mg/day
Placebo 18 months
Parham,
2008
[33]
Iran DM
CCT
21/18 Age (years): 52.0 ± 9.3/54.5 ± 9.2
Disease duration (years): 12.0 ± 6.1/
10.5 ± 5.7
Zinc 30 mg Placebo 3 months
Williams,
2007
[34]
USA DN
DM1&2
RPC
122/90 Age (years): 52.3 ± 11.4/51.3 ± 10.2 Pyridoxamine
(250 mg twice
daily)
Placebo 24 weeks
Giannini,
2007
[35]
Italy DN
DM1
CCT
10/10 Age (years): 18.87 ± 2.91
Disease duration
(years):12.62 ± 3.37
Vit E 1200 mg/day Placebo 24 weeks
Farvid, 2005
(1, M)
[36]
Iran DN
DM2
RPC
16/18 Age (years): 52 ± 8/50 ± 9
BMI (kg/m
2
): 27.7 ± 4.7/27.4 ± 3.7
Disease duration (years):
9.0 ± 6.2/8.3 ± 4.3
Mg 200 mg/day + Zn
30 mg/day
Placebo 3 months
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ZHONG ET AL.
TABLE 2 (Continued)
Study
Country Type
Sample size
(antioxidant/
control)
Population characteristics
(antioxidant/control)
Intervention
Duration of
intervention
Diabetic
nephropathy Antioxidant group Control group
Farvid, 2005
(2, V)
[36]
Iran DN
DM2
RPC
18/18 Age (years): 50 ± 9/50 ± 9
BMI (kg/m
2
): 27.5 ± 4.7/27.4 ± 3.7
Disease duration (years):
9.2 ± 5.3/8.3 ± 4.3
Vit C 200 mg/day +
Vit E 100IU/day
Placebo 3 months
Farvid, 2005
(3, MV)
[36]
Iran DN
DM2
RPC
17/18 Age (years): 50 ± 9/50 ± 9
BMI (kg/m
2
): 29.2 ± 4.0/27.4 ± 3.7
Disease duration (years):
7.7 ± 4.7/8.3 ± 4.3
Mg 200 mg/day + Zn
30 mg/day + Vit
C 200 mg/day +
VitE 100 IU/day
Placebo 3 months
Gaede,
2001
[37]
Denmark DN
DM2
CCT
14/14 Age (years): 58.7 ± 7.3
Disease duration (years): 12.2 ± 4.4
Vit C 1250 mg/day +
Vit E 680 IU/day
Placebo 4 weeks
Nonalcoholic fatty liver disease (NAFLD)
Bril, 2019(1)
[3]
USA DM2
RPC
36/32 Age (years): 60 ± 9/57 ± 11
BMI (kg/m
2
): 33.8 ± 4.6/33.6 ± 4.0
Vit E 400 IU/day Placebo 18 months
Bril, 2019(2)
[3]
USA DM2
RPC
37/32 Age (years): 60 ± 6/57 ± 11
BMI (kg/m
2
): 35.2 ± 4.3/33.6 ± 4.0
Vit E 400 IU/day +
pioglitazone
45 mg/day
Placebo 18 months
Alavinejad,
2016
[38]
Iran DM2
RPC
28/26 Age (years): 60 ± 5/59 ± 9
BMI (kg/m
2
): 28.6 ± 4.6/29.5 ± 3.6
L‐Carnitine
750 mg/day
Placebo 3 months
Bae, 2015
[39]
Korea DM
RPC
39/39 Age (years): 50.6 ± 9.3/52 ± 9.4
BMI (kg/m
2
): 28.2 ± 2.6/26.7 ± 3.7
Carnitine‐orotate
complex
2472 mg/day
Placebo 12 weeks
Hong, 2014
[40]
Korea DM 26/26 Age (years): 51.5 ± 9.4/52.0 ± 9.6
BMI (kg/m
2
): 27.2 ± 2.6/27.0 ± 3.1
Carnitine‐orotate
complex 900 mg/
day + metformin
750 mg/day
Metformin
750 mg/
day
12 weeks
Periodontitis
Anton, 2021
[41]
Romania DM2
RPC
25/25 Age (years): 53.24 ± 3.4/52.21 ± 3.1
BMI (kg/m
2
): 26.06 ± 3.33/
27.18 ± 2.15
Scaling and root
planing +
melatonin
Scaling and
root
planing +
placebo
8 weeks
Gholinezhad,
2020
[42]
Iran DM2
RPC
21/21 Age (years): 52.81 ± 6.44/
51.62 ± 5.95
BMI (kg/m
2
): 26.06 ± 3.33/
27.18 ± 2.15
Ginger 2 g/day Placebo
2 g/day
8 weeks
Zare Javid,
2020
[43]
Iran DM2
RPC
22/22 Age (years): 53.72 ± 6.68/
51.45 ± 5.03
BMI (kg/m
2
): 27.36 ± 2.1/
27.21 ± 2.19
Disease duration (years):
7.77 ± 2.59/7.36 ± 2.87
Melatonin
250 mg/day
Placebo
250 mg/
day
8 weeks
Kunsongkeit,
2019
[44]
Thailand DM2
RPC
15/16 Age (years): 59.87 ± 11.3/
57.94 ± 14.0
Disease duration (years):
7.86 ± 4.16/7.64 ± 4.42
Vit C 500 mg/day Placebo 2 months
Zare Javid,
2019
[45]
Iran DM2
RPC
21/22 Age (years): 49.1 ± 7.4/50.9 ± 8.9
BMI (kg/m
2
): 29.3 ± 4.9/28.3 ± 4.8
Resveratrol
480 mg/day
Placebo 4 weeks
Zare Javid,
2019 (G)
[46]
Iran DM2
RPC
21/21 Age (years): 52.81 ± 6.44/
51.62 ± 5.95
Ginger 2 g/day Placebo 8 weeks
(Continues)
ZHONG ET AL.
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some studies did not describe the method of random assignment of
included cases, and did not describe whether the assignment was
hidden. The demographics of the patients are shown in Table 2.
3.3 |Impact of antioxidant supplementation on
glycemic control in diabetic patients
A total of 23 studies reported on the effect of antioxidants
supplementation on glucose control. The results of meta‐analysis
showed that: individuals with diabetes on antioxidants supplements
had lower FPG levels (SMD: −0.21 [95% CI: −0.33, −0.10], p< 0.001)
(Figure 3A) and HbA1c (MD: −0.41 [95% CI: −0.63, −0.18],
p< 0.001), respectively, when compared with the control group
without antioxidants (Figure 3B). For the subgroup analysis,
individuals with T2DM on antioxidants supplements had lower FPG
levels (SMD: −0.25 [95% CI: −0.42, 0.08], p= 0.005) and HbA1c
(MD: −0.48 [95% CI: −0.80, 0.16], p= 0.004), respectively, when
compared with the control group without antioxidants (Table S1);
individuals from mixed or unclear group on antioxidants supplements
also had lower FPG levels (SMD: −0.18 [95% CI: −0.34, 0.02],
p= 0.03) and HbA1c (MD: −0.33 [95% CI: −0.63, 0.03], p= 0.03),
respectively, when compared with the control group without
antioxidants (Table S1). Begg's test and Egger's test showed no
significant publication bias for FPG (P
(B)
= 1.4738, P
(E)
= 0.5185) and
HbA1c(P
(B)
= 1.6810, P
(E)
= 0.3818).
3.4 |Impact of antioxidant supplementation on
systemic antioxidant capacity in diabetic patients
A total of 11 studies reported on the effect of antioxidants
supplementation on overall antioxidant capacity. The results of
meta‐analysis showed that: individuals with diabetes on antiox-
idants supplements had higher TAC levels (SMD: 0.44 [95% CI:
0.24, 0.63], p<0.001) (Figure 4A) and lower MDA levels (SMD: −
0.82 [95% CI: −1.24, −0.41], p< 0.001), respectively, when
compared with the control group without antioxidants
(Figure 4B). For the subgroup analysis, individuals with T2DM on
antioxidants supplements had lower MDA levels (SMD: −1.08
[95% CI: −1.71, 0.45], p< 0.001), respectively, when compared
with the control group without antioxidants (Table S1); individuals
from mixed or unclear group on antioxidants supplements had
higher TAC levels (SMD: 0.55 [95% CI: 0.31, 0.79], p< 0.001) and
lower MDA levels (SMD: −1.08 [95% CI: −1.71, −0.45], p< 0.001),
respectively, when compared with the control group without
antioxidants (Table S1).Begg'stestandEgger'stestshowedno
significant publication bias for TAC (P
(B)
= 0.3865, P
(E)
= 0.6914).
However, there may be a publication bias for MDA levels
(P
(B)
= 1.9383, P
(E)
= 0.0387), and more high‐quality studies are
needed to confirm the results.
3.5 |Impact of antioxidants supplementation on
markers of renal function in diabetic patients
A total of 16 studies reported on the effect of antioxidants
supplementation on markers of renal function. The results of meta‐
analysis showed that: individuals with diabetes on antioxidants
supplements had higher eGFR levels (SMD: 0.21 [95% CI: 0.08,
0.34], p= 0.002) (Figure 5A) and lower serum creatinine levels
(SMD: −0.17 [95% CI: −0.29, −0.06], p= 0.002) (Figure 5C) and lower
UACR levels (SMD: −0.38 [95% CI: −0.72, −0.04], p= 0.03)
(Figure 5E), respectively, when compared with the control group
without antioxidants. However, antioxidants supplementation did not
affect the levels of BUN (SMD: −0.30 [95% CI: −0.90, 0.30], p= 0.32)
(Figure 5B) and CG (SMD: −0.14 [95% CI: −0.43, 0.14], p= 0.33) in
comparison to the control group without antioxidants (Figure 5D).
For the subgroup analysis, only individuals with T2DM on antiox-
idants supplements had higher eGFR levels (SMD: 041 [95% CI: 0.24,
0.59], p< 0.001) and lower serum creatinine levels (SMD: −0.18 [95%
CI: −0.33, −0.04], p= 0.01), respectively, when compared with the
control group without antioxidants (Table S1). Begg's test and Egger's
test showed no significant publication bias for eGFR (P
(B)
= 1.0547,
P
(E)
= 0.4313), serum creatinine (P
(B)
= 1.9397, P
(E)
= 0.3534), UACR
(P
(B)
= 1.2895, P
(E)
= 0.5226).
TABLE 2 (Continued)
Study
Country Type
Sample size
(antioxidant/
control)
Population characteristics
(antioxidant/control)
Intervention
Duration of
intervention
Diabetic
nephropathy Antioxidant group Control group
BMI (kg/m
2
): 26.06 ± 3.33/
27.18 ± 2.15
Bazyar,
2018
[47]
Iran DM2
RPC
22/22 Age (years): 53.72 ± 6.68/
51.45 ± 5.03
Melatonin
250 mg/day
Placebo 8 weeks
Zare Javid,
2017
[48]
Iran DM2
RPC
21/22 Age (years): 49.1 ± 7.4/50.9 ± 8.9
BMI (kg/m
2
): 29.3 ± 4.9/28.3 ± 4.8
Resveratrol
480 mg/day
Placebo 4 weeks
Note: All values are presented as mean ± standard deviation or median (IQR).
Abbreviations: CCT, cross control test; RPC, randomized, placebo‐controlled.
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3.6 |Impact of antioxidants supplementation on
liver function in diabetic patients
A total of four studies reported on the effect of antioxidants
supplementation on liver function. The results of meta‐analysis showed
that: individuals with diabetes on antioxidants supplements had lower
AST levels (MD: −19.29 [95% CI: −33.12, −5.47], p= 0.006) (Figure 6A)
and lower ALT levels (SMD: −45.99 [95% CI: −65.13, −26.84],
p< 0.001) (Figure 6B) and higher HDL (SMD: 1.57 [95% CI: 0.25,
2.89], p= 0.02) (Figure 6C), respectively, when compared with the
control group without antioxidants (Figure 3B). However, antioxidants
supplementation did not affect the levels of LDL (SMD: 3.89 [95%
CI: −2.13, 9.91], p= 0.21) (Figure 6D)incomparisontothecontrol
group without antioxidants. Begg's test and Egger's test showed no
significant publication bias for AST (P
(B)
= 1.7037, P
(E)
= 0.5648), ALT
(P
(B)
= 1.7037, P
(E)
= 0.3033), HDL (P
(B)
= 1.2659, P
(E)
= 0.6290).
FIGURE 3 Forest plot evaluating the effects of antioxidants on FPG (A) and HbA1c (B) in diabetic patients and compared with controls
group. FPG, fasting plasma glucose; HbA1c, hemoglobin A1c
ZHONG ET AL.
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3.7 |Antioxidant supplementation improves
periodontal status in diabetic patients with
periodontitis
A total of six studies reported on the effect of antioxidants
supplementation on periodontal status. The results of meta‐analysis
showed that: antioxidants improved PD levels (MD: −0.77 [95% CI:
−1.31, −0.23], p= 0.005) (Figure 7A)andCALlevels(MD:−0.57 [95%
CI: −1.12, −0.01], p= 0.04) (Figure 7B) in diabetic patients, respectively,
when compared with the control group without antioxidants
(Figure 3B). Begg's test and Egger's test showed no significant
publication bias for PD (P
(B)
= 1.8269, P
(E)
= 0.2400), CAL (P
(B)
= 1.9202,
P
(E)
= 0.1752).
4|DISCUSSION
DM is a group of chronic metabolic diseases characterized by
hyperglycemia, which is caused by a combination of genetic and
environmental factors. It has become one of the major chronic
diseases affecting the health of people around the world. Complica-
tions from diabetes affect almost every tissue in the body and
diabetes is a leading cause of cardiovascular morbidity and mortality,
blindness, kidney failure, and amputation.
[49]
Diabetes and impaired
glucose tolerance increase the risk of cardiovascular disease by three
to eight times.
[5]
In addition, clinical data suggest that 30%–40% of
patients develop at least one complication within 10 years of the
onset of diabetes. Unfortunately, although existing antidiabetic
drugs, such as biguanides and sulfonylureas, are effective in
regulating hyperglycemia, they do not completely prevent the
occurrence and development of its complications.
[50]
Studies
have shown that the complications of diabetes are related to oxidative
stress. Persistent hyperglycemia can disrupt mitochondrial function, lead
to overproduction of ROS, and lead to oxidative damage to islet cells
and vascular tissue.
[5]
Since pancreatic cells contain very low levels of
antioxidant enzymes, they may be more susceptible to the cytotoxic
effects of ROS.
[51]
Antioxidants can improve insulin resistance by
increasing the sensitivity of insulin receptors; can improve glucose
metabolism disorder by improving glucose uptake and metabolism; and
can protect beta cells and promote insulin release.
[50,52]
As indicated in
the meta‐analysis, patients' FPG and HbA1c levels were significantly
decreased and their overall antioxidant capacity was significantly
enhanced after taking antioxidants.
Diabetic nephropathy is one of the most serious micro-
vascular complications of diabetes. Diabetic nephropathy devel-
ops over time, reaching a peak incidence after 10–20 years of
persistent diabetes, affecting 45% of patients with diabetes, and
is the leading cause of end‐stage renal disease (ESRD).
[53]
FIGURE 4 Forest plot evaluating the effects of antioxidants on TAC (A) and MDA (B) in diabetic patients and compared with controls group.
MDA, malondialdehyde; TAC, total antioxidant capacity
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FIGURE 5 Forest plot evaluating the effects of antioxidants on eGFR (A), BUN (B), serum creatinine (C), CG (D) and UACR (E) in diabetic
patients and compared with the control group. BUN, blood urea nitrogen; CG, Cockcroft‐Gault formula to estimate of creatinine clearance;
eGFR, estimated glomerular filtration rate; UACR, urinary albumin‐to‐creatinine ratio
ZHONG ET AL.
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Diabetes leads to renal microvascular rupture, progressive
damage to glomerular capillaries and tubulointerstitial levels,
and patients present with persistent decreases in proteinuria and
glomerular filtration rate (GFR).
[49]
Various factors affect the
occurrence and progression of diabetic nephropathy. Hyper-
glycemia increases free radical production and leads to oxidative
stress, which plays an important role in the pathogenesis of DN
and its progression to end‐stage renal disease (ESRD).
[54]
Studies
have shown that oxidative stress is directly related to renal
podocyte injury, proteinuria, and renal tubulointerstitial fibro-
sis.
[55]
Studies in animal models have shown that antioxidant
therapy has beneficial effects.
[56,57]
However, the results of
antioxidant therapy in patients with DN are limited and partially
conflicting.
[15,17,32,58]
Therefore, we collected data from 25
studies to evaluate the role of antioxidants in the treatment of
DN. The results of meta‐analysis showed that compared with the
control group, antioxidant significantly increased eGFR level,
decreased serum creatinine value, and decreased UACR value in
DN patients. However, existing studies cannot prove that
antioxidants have a beneficial effect on BUN and CG levels in
patients. Overall, the effect of antioxidants on PATIENTS with
DN was positive.
Nonalcoholic fatty liver disease, which results from the accumu-
lation of fat droplets in human liver cells, is increasing globally due to
the prevalence of diabetes and obesity, as well as sedentary
lifestyles.
[59]
NAFLD is estimated to affect 24% of the global
population and is more common in people with type 2 diabetes
(T2DM).
[60]
The development of NAFLD is associated with a number
FIGURE 6 Forest plot evaluating the effects of antioxidants on AST (A), ALT (B), HDL(C) and LDL (D) in diabetic patients and compared with
the control group. AST, aspartate aminotransferase; ALT, alanine aminotransferase; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein
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of factors, among which insulin resistance and oxidative stress seem
to play an important role in the accumulation of fat droplets in
hepatocytes.
[38,61]
Therefore, we collected data from four existing
studies to evaluate the role of antioxidants in the treatment of
diabetes with NAFLD. Results of meta‐analysis showed that
antioxidants significantly reduced AST and ALT levels and increased
HDL levels in NAFLD patients compared with the control group.
However, existing studies cannot prove that antioxidants have a
beneficial effect on patients' LDL levels. Currently, there are few
studies on the treatment of diabetes with NAFLD by antioxidants,
and the above results need to be confirmed by more high‐quality
studies.
Periodontitis is a common, chronic inflammatory condition
that affects the supporting tissues surrounding teeth. Diabetes is
currently considered a risk factor for the development of
periodontitis and increases its prevalence, severity, and progres-
sion. The prevalence of severe periodontitis was reported to be
39%−59.6% higher in patients with diabetes than in patients
without diabetes.
[47]
Studies have shown that increased peri-
odontal inflammation is potentially associated with elevated
serum HbA1c levels in diabetic patients, which may be related
to increased oxidative stress in diabetic patients.
[41]
Therefore,
we collected data from eight studies designed to get a robust
evidence for clinical decisions. To our knowledge, this is the first
systematic analysis of data which was pooled from eight studies
that evaluated the role of antioxidants in the treatment of
diabetes with periodontitis. The results of meta‐analysis showed
that antioxidants significantly reduced the depth of PD and the
degree of clinical attachment loss of the affected teeth.
However, this systematic review has the following limitations: (1)
The types of diabetes patients included were different, some were
type 1 diabetes and some were type 2 diabetes; (2) The large
difference in the sample size of the included studies may cause some
heterogeneity; (3) Only English literature was included in this study,
which may affect the extrapolation of the results; (4) The types of
antioxidants included in the study were diverse, and it was not clear
which antioxidant was the most effective; (5) The effect in many
occasions was assessed by very few studies; thus, the evidence to
support the findings and conclusions may be limited. For more
precise findings and accurate conclusions, more high‐quality trials are
needed to evaluate the beneficial effects of antioxidants on diabetes
and its complications.
In conclusion, there are 36 studies included in present systematic
review and meta‐analysis for evaluating the association between
antioxidants and diabetes complications. The results of this study
indicate that antioxidant therapy is effective in the treatment of the
above three complications of diabetes.
ACKNOWLEDGMENTS
This study was supported by the National Natural Science Fund of
China (No. 82101720); Natural Science Foundation of Guangxi in
China (No.2021GXNSFBA220010); Natural Science Foundation of
Hunan Province (No. 2020JJ5500); Key Lab for Clinical Anatomy &
Reproductive Medicine of Hengyang City (2017KJ182).
FIGURE 7 Forest plot evaluating the effects of antioxidants on PD (A) and CAL (B) in diabetic patients and compared with the control group.
CAL, clinical attachment loss; PD, pocket depth
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CONFLICTS OF INTEREST
The authors declare no conflicts of interest.
AUTHOR CONTRIBUTIONS
Ou Zhong, Jialin Hu, Linlin Hu and Xiaocan Lei conceived the
research, analyzed the data and wrote the manuscript. Jinyuan
Wang and Yongpeng Tan performed the data collection and
statistical analysis. All the authors approved the manuscript for
submission.
DATA AVAILABILITY STATEMENT
All the data are available upon request from the corresponding
author.
ORCID
Xiaocan Lei http://orcid.org/0000-0001-7666-5082
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SUPPORTING INFORMATION
Additional supporting information can be found online in the
Supporting Information section at the end of this article.
How to cite this article: O. Zhong, J. Hu, J. Wang, Y. Tan, X.
Lei, J. Biochem. Mol. Toxicol.2022, e23038.
https://doi.org/10.1002/jbt.23038
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