Efficacy and safety of saxagliptin in patients with type 2 diabetes: A systematic review and meta-analysis
Efficacy and safety of saxagliptin in patients with type 2 diabetes: A systematic review and meta-analysis
Peng Men 0 1
Xiao-tong Li 0 1
Hui-lin Tang 0 1
Suo-di Zhai 0 1
0 Department of Pharmacy, Peking University Third Hospital , Beijing , China
1 Editor: Stephen L Atkin, Weill Cornell Medical College Qatar , QATAR
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: The authors received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
To evaluate the comparative efficacy and safety of saxagliptin for type 2 diabetes (T2D).
A systematic search of PubMed, Embase, the Cochrane Library, Web of Science,
ClinicalTrials.gov and two Chinese databases for randomized controlled trials (RCTs) comparing
saxagliptin with placebo or active comparators was performed up to July 2017. A
complementary search was done to cover literature until March 2018. For continuous data,
estimates were pooled using inverse variance methodology to calculate weighted mean
differences (WMDs). Dichotomous data were presented as Mantel-Haenzel risk ratios
Thirty-nine references of 30 RCTs involving 29,938 patients were analyzed. Compared
with placebo, saxagliptin significantly reduced glycated hemoglobin (HbA1c, WMD
-0.52%, 95% CI -0.60 to -0.44) and fasting plasma glucose (WMD -13.78 mg/dL, 95% CI
-15.31 to -12.25), and increased the proportion of patients achieving HbA1c <7% (RR
1.64, 95% CI 1.53 to 1.75). When combined with submaximal-dose metformin, saxagliptin
significantly increased the proportion of patients achieving HbA1c <7% compared with
acarbose (RR 2.38, 95% CI 1.17 to 4.83) and uptitrated metformin (RR 1.30, 95% CI 1.04
to 1.63). Saxagliptin was similar to other DPP-4 inhibitors but inferior to liraglutide and
dapagliflozin on glycemic control. Saxagliptin significantly decreased the incidences of
overall adverse events compared with acarbose (RR 0.71, 95% CI 0.57 to 0.89) and
liraglutide (RR 0.41, 95% CI 0.24 to 0.71) when added to metformin. Weight gain and
hypoglycemia with saxagliptin was slightly but significantly higher than placebo and lower than
sulfonylureas. Saxagliptin did not increase the risk of arthralgia, heart failure, pancreatitis
and other adverse events.
Generally, saxagliptin has similar efficacy compared with most oral antidiabetic drugs and
may be more effective than acarbose, while having a better safety profile than both
acarbose and sulfonylureas.
Type 2 diabetes (T2D) is a chronic disease rapidly increasing in prevalence that imposing
enormous medical and economic burdens on on individuals, families, and national health
systems worldwide. It is estimated that approximately 415 million people in the world had
diabetes in 2015, and this figure is projected to increase to 642 million by 2040 [
spending on diabetes accounted for 11.6% of total health expenditure worldwide in 2015 [
diversity of antidiabetic drugs to treat the condition is now available, including metformin,
sulfonylureas, thiazolidinediones, α-glucosidase inhibitors, prandial glucose regulators,
sodiumglucose cotransporter 2 (SGLT2) inhibitors, and insulin in various forms. Because of the
progressive nature of diabetes, clinicians and patients often experience difficulty in achieving and
sustaining glycemic control. Utilization of antidiabetic drugs should be based on the individual
patient's characteristics and preferences and balance the need to optimize the benifits of
glycaemic control with the need to limit the risk of adverse effects.
Dipeptidyl peptidase 4 (DPP-4) inhibitors (gliptins) are a relatively new class of oral
antidiabetic drugs for the treatment of type 2 diabetes. They act by increasing postprandial
concentrations of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide
(GIP) [3±4]. GLP-1 and GIP stimulate insulin secretion in a glucose-dependent manner,
suppressing glucagon secretion and slowing gastric emptying. The American Diabetes Association
and the European Association for the Study of Diabetes have advocated the use of DPP-4
inhibitors as first-line agent in circumstances where metformin is contraindicated or not
tolerated, or within a dual or triple agent regimen [
]. Saxagliptin is an orally active, once-daily,
selective and reversible inhibitor of DPP-4 enzyme indicated/approved as an adjunct to diet
and exercise to improve glycemic control in adults with type 2 diabetes [
With the growing number of pharmacological options for treating type 2 diabetes, there is
a need for state-of-the-art evidence to inform clinical decisions about differences among the
various medications. Recent systematic reviews and meta analyses of DPP-4 inhibitors have
mainly focused on the clinical profiles of these drugs as a whole class [8±11]. For saxagliptin,
only one meta-analysis [
] examined its efficacy based on 14 phase 2 and 3 trials, without
systematically database searches. This systematic review synthesized currently available evidence
to provide a better understanding of the comparative efficacy and safety of saxagliptin in
treating type 2 diabetes.
Data sources and search strategy
This meta-analysis of the available data on saxagliptin was undertaken using a predetermined
protocol, and is reported in accordance with the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) statement (see S1 Text) [
]. Relevant studies for the
analysis were selected by searching PubMed, Embase, the Cochrane Library, Web of Science,
and 2 Chinese databases [China National Knowledge Infrastructure (CNKI) and Chinese
Biomedical Literature Database (CBM)] up to the end of July 2017. A complementary search was
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performed in order to include the most recent articles (published before March 2018). The
generic drug name ªsaxagliptinº was used as the only search term. If necessary, specific filters
for retrieving randomized controlled trials (RCTs) conducted in humans were incorporated
into the search string. We considered all potentially eligible studies for review, irrespective of
the primary outcomes or language. We also performed a manual search using the reference
lists of published reviews of saxagliptin.
The research questions and eligibility criteria for the systematic review conformed with the
PICOS (participants, interventions, comparators, outcomes and study design) approach.
Studies meeting the following criteria were considered for inclusion:
· Participants: patients over 18 years of age with type 2 diabetes.
· Interventions: saxagliptin used in the treatment of type 2 diabetes (as monotherapy or in dual
or triple therapy).
· Comparators: placebo or other active antidiabetic interventions (as monotherapy or in dual
or triple therapy).
· Outcomes: glycated hemoglobin (HbA1c), proportion of patients achieving HbA1c targets of
<7%, fasting plasma glucose (FPG) concentration, overall and serious adverse events, body
weight, confirmed hypoglycemia, heart failure, pancreatitis, arthralgia, and other adverse
events [hypertension, urinary tract infection, upper respiratory tract infection,
nasopharyngitis]. For continuous data, the mean change from baseline was examined.
· Study type: RCTs involving >150 patients.
Study selection and data extraction
The titles and abstracts of all retrieved citations were independently screened by 2 reviewers to
identify potentially relevant studies. The full texts of relevant citations were then retrieved to
determine their suitability for inclusion. If there were any discrepancies between the 2
reviewers, a third reviewer became involved.
Data were independently abstracted by the 2 principal reviewers and any discrepancies
were resolved by consensus. The data extracted included study characteristics (design, total
number of participants, trial duration, antidiabetic treatments, patient inclusion and exclusion
criteria), patient demographics (age, sex, baseline HbA1c levels), and pre-specified efficacy
and safety outcomes. For extension studies, if the treatment assignment was switched from
placebo to saxagliptin, only the outcome data up to that point were documented. Only
information that related to dosages currently approved by the US Food and Drug Administration
(FDA) or the European Medicines Agency (EMA) were abstracted. Corresponding authors
were contacted for data not provided within studies, or when outcomes were presented in an
unsuitable format for data synthesis.
Two reviewers independently applied the Cochrane Risk of Bias tool to assessed the risk of
bias in the RCTs. The following methodological features relevant to the minimization of bias
were assessed: randomization, random allocation concealment, masking of treatment
allocation, blinding, incomplete outcomes data, selective reporting, and other items. The following
judgements were used: low risk, high risk, or unclear risk (either lack of information or
uncertainty regarding the potential for bias). Disagreements were resolved by consensus with a third
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Data synthesis and analysis
Outcomes were pooled using Review Manager 5.2 software (RevMan, Cochrane, London,
UK). For continuous data, estimates were pooled using inverse variance methodology to
calculate weighted mean differences (WMDs). Dichotomous data were presented as
Mantel-Haenzel risk ratios (RRs). All results were estimated from each study with 95% confidence intervals
(CIs). Heterogeneity was assessed using the chi-square test and the I2 statistic. If I2 was 50%, a
fixed-effect model with the Mantel-Haenszel method was used; otherwise, the random-effect
model was adopted.
Where studies did not report standard deviations (SDs) explicitly, these were derived from
the available published information. If possible, standard errors (SEs) were calculated from
CIs. If these data were unavailable, they were derived from p-values for changes from baseline.
All trials were included in at least one of the analyses, and each trial could be used in multiple
sets of analyses. Data were reported first from studies involving placebo comparisons, and
then from studies involving active comparators.
The selection process for articles included in the systematic review is shown in Fig 1. From the
5773 citations identified by the initial and complementary literature searching, 38 references
[14±51], including 30 trials involving 29,938 participants, ultimately met the inclusion criteria
for the meta-analysis. The study characteristics and the demographics of the patient
populations in the retrieved studies were comparable (Table 1). Enrolled patients in these RCTs had a
mean age of 42.0 to 72.6 years. The mean duration of type 2 diabetes ranged from 0.4 to 16.7
years, with mean baseline HbA1c levels between 7.6% and 10.7%.
Quality of the included studies
A risk of bias summary is shown in S1a Fig, and an assessment of the risk of bias for each of
the studies selected is shown in S1b Fig. Random sequence generation was adequate in 25
trials, and allocation concealment was adequately described in 16 trials. Two trials were
considered to be at high risk of performance and detection bias. All studies were judged to be at low
risk of attrition, reporting and other bias.
Glycated hemoglobin (HbA1c). In comparison with placebo, saxagliptin produced
significantly greater reductions in HbA1c (WMD −0.52%, 95% CI −0.60 to −0.44; p < 0.00001;
Fig 2a), whether used as monotherapy (WMD −0.50%, 95% CI −0.62 to −0.37; p < 0.00001) or
add-on therapy (WMD −0.52%, 95% CI −0.62 to −0.43; p < 0.00001). Both the 2.5 mg/day and
5 mg/day dosages of saxagliptin produced significant improvements in HbA1c, with similar
absolute effect sizes.
Overall, saxagliptin produced similar reduction in HbA1c compared with active
comparators when added to metformin (WMD 0.01%, 95% CI −0.11 to 0.13; p = 0.89; Fig 2b).
Saxagliptin significantly reduced HbA1c in comparison with acarbose (WMD −0.12%, 95% CI −0.22
to −0.02; p = 0.02), but not compared with liraglutide (WMD 0.27%, 95% CI 0.09 to 0.45;
p = 0.003) or dapagliflozin (WMD 0.32%, 95% CI 0.11 to 0.53; p = 0.003). Saxagliptin produced
similar reduction compared with metformin (WMD -0.30%, 95% CI -0.74 to 0.13; p = 0.17),
sulfonylureas (WMD 0.14%, 95% CI -0.02 to 0.30; p = 0.08), sitagliptin (WMD 0.10%, 95% CI
-0.01 to 0.20; p = 0.07), vildagliptin (WMD 0.02%, 95% CI -0.15 to 0.19; p = 0.79) and
repaglinide (WMD 0.30%, 95% CI -0.18 to 0.78; p = 0.22).
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Fig 1. Selection process for articles in the systematic review.
A significantly greater proportion of patients treated with saxagliptin also achieved a target
HbA1c of <7% compared with placebo (RR 1.64, 95% CI 1.53 to 1.75; p < 0.00001; S2a Fig),
whether used as monotherapy (RR 1.53, 95% CI 1.32 to 1.77; p < 0.00001) or add-on therapy
(RR 1.67, 95% CI 1.55 to 1.81; p < 0.00001). Similar results was shown when compared with
metformin (RR 1.30, 95% CI 1.04 to 1.63; p = 0.02) and acarbose (RR 2.38, 95% CI 1.17 to 4.83;
p = 0.02). However, no significant differences were observed in comparisons of saxagliptin
with other active comparators (S2b Fig).
Fasting plasma glucose (FPG). In comparison with placebo, saxagliptin produced
significantly greater reductions in FPG (WMD −13.78 mg/dL, 95% CI −15.31 to −12.25; p < 0.00001;
Fig 3a), whether used as monotherapy (WMD −14.89 mg/dL, 95% CI −20.14 to −9.64;
p < 0.00001) or add-on therapy to other antidiabetic agents (WMD −13.68 mg/dL, 95%
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CI −15.28 to −12.08; p < 0.00001). Both the 2.5 mg/day and 5 mg/day dosages of saxagliptin
produced significant improvements in FPG.
When added to metformin, saxagliptin produced a significantly smaller reduction in FPG
compared with sulfonylureas (WMD 9.05 mg/dL, 95% CI 6.18 to 11.93; p < 0.00001),
liraglutide (WMD 7.60 mg/dL, 95% CI 1.76 to 13.44; p = 0.01) and dapagliflozin (WMD 18.00 mg/
dL, 95% CI 10.10 to 25.90; p < 0.00001). However, no significant differences were observed
when saxagliptin was compared with other active comparators (Fig 3b), including sitagliptin
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PLOS ONE | https://doi.org/10.1371/journal.ponhFeti.tg0ps12:9.//7Mdo3ei2.ao1nrgc/1hM0a.an1y3g7e21o2/fj,oH2ur0bn1Aa8l1.pcofnreo.0m19b7a3s2e1li.ng0e0(2a. saxagliptin vs placebo; b. saxagliptin vs active comparators). 8 / 18
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(WMD -0.13 mg/dL, 95% CI -11.44 to 11.18; p = 0.98) and vildaglitpin (WMD 5.52 mg/dL,
95% CI -0.78 to 11.81; p = 0.09).
Overall and serious adverse events. Generally, the incidences of overall (versus placobo:
RR 1.01, 95% CI 0.97 to 1.05; p = 0.77; Fig 4a) and severe (versus placobo: RR 1.01, 95% CI 0.96
to 1.06; p = 0.78; S3 Fig) treatment-related adverse events did not increase in the treatment of
saxagliptin. Moreover, saxagliptin significantly reduced overall adverse events compared with
acarbose (RR 0.71, 95% CI 0.57 to 0.89; p = 0.03; Fig 4b) and liraglutide (RR 0.41, 95% CI 0.24
to 0.71; p = 0.001) when added to metformin.
Hypoglycemia. Compared with placebo, saxaglitpin significantly but slightly increased
the incidences of hypoglycemia (RR 1.13, 95% CI 1.05 to 1.21; p = 0.0009; Fig 5a). Compared
with sulfonylureas, saxaglitpin significantly reduced the risk of hypoglycemia by 95% (RR 0.05,
95% CI 0.01 to 0.23; p = 0.0002; Fig 5b). No significant differences were observed in
comparison with other active comparators, including other DPP-4 inhibitors.
Body weight. In comparison with placebo, treatment with saxaglipitin was associated
with a significant but slight increase of body weight (WMD 0.42 kg, 95% CI 0.26 to 0.59;
p < 0.00001; S4a Fig). Saxagliptin was inferior to liraglutide (WMD 5.10 kg, 95% CI 1.66 to
8.54; p = 0.004; S4b Fig) and dapagliflozin (WMD 2.40 kg, 95% CI 1.69 to 3.11; p < 0.00001).
However, treatment with saxagliptin was associated with significantly less effect on body
weight than sulfonylureas (WMD −2.34 kg, 95% CI −3.31 to −1.36; p < 0.00001). In
comparison with other DPP-4 inhibitors, changes in body weight were similar.
Other adverse events. The incidences of pancreatitis (RR 1.13, 95% CI 0.65 to 1.96;
p = 0.66; S5a Fig) and heart failure (RR 0.99, 95% CI 0.89 to 1.10; p = 0.85; S5b Fig) did not
differ significantly between saxagliptin and controls (placebo and sulfonylureas). The risk of
arthralgia did not differ significantly between saxagliptin and placebo (RR 1.02, 95% CI 0.92 to
1.13; p = 0.66; S5c Fig), Compared with sitagliptin, saxagliptin could significantly reduced the
risk of arthralgia (RR 0.20, 95% CI 0.04 to 0.90; p = 0.04; S5d Fig), but not compared with other
active treatments. Treatment with saxagliptin was not associated with any increased risks of
upper respiratory tract infection, urinary tract infection and nasopharyngitis compared with
both placebo and active comparators (p > 0.05). See S5e±S5j Fig. for forest plots of adverse
This meta-analysis of the available literature on saxagliptin aimed to assess its clinical efficacy
and safety in patients with type 2 diabetes. The findings of the analysis indicate that treatment
with saxagliptin can lead to significant decreases of HbA1c and FPG compared with placebo,
both when given as monotherapy or add-on therapy to other treatments, including metformin,
sulfonylureas, thiazolidinediones, dapagliflozin and insulin. Mean placebo-adjusted HbA1c
and FPG levels in saxagliptin add-on therapy were lowered by comparable amounts to
saxagliptin monotherapy. When combined with submaximal-dose metformin, saxagliptin
significantly increased the proportion of patients achieving HbA1c <7% compared with acarbose
and uptitrated metformin. Generally, efficacy on glycemic control of saxagliptin was similar to
sitaglitpin and vildagliptin, while inferior to liraglutide and dapagliflozin. More direct
comparisons with other active comparators in future trials may provide further evidence of the efficacy
of saxagliptin in comparison with other active treatments.
Saxagliptin is generally well tolerated, with no increased risk of overall and serious adverse
events as monotherapy and combination therapy. Additionally, saxagliptin group experienced
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less overall adverse events than acarbose and liraglutide groups when combined with
metformin, indicating its favorable safety profile in patients with T2D. Compared with sulfonylureas,
saxagliptin had a significant better effect on hypoglycemia and body weight gain. Treatment of
saxagliptin was shown to be with a minimal increase of hypoglycemia, which mainly
depending on the result from the included Saxagliptin Assessment of Vascular Outcomes Recorded in
Patients with Diabetes Mellitus -Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53)
trial. Patients in that trial were permitted various concomitant antihyperglycaemic therapies at
the doctor's discretion. A post-hoc analysis  of SAVOR-TIMI 53 trial found that
hypoglycemia rates (any or major) were increased with saxagliptin in patients taking sulfonylureas,
not in those taking insulin. A pooled analysis also found that saxagliptin was not associated
with increased reported or confirmed hypoglycemia when use of sulfonylurea was excluded
. Thus, lower doses of sulfonylureas might be required to reduce risk of hypoglycaemia.
Saxagliptin improves the sensitivity of pancreatic islets (α- and β-cells) to glucose, inhibits the
production of glucagon, and stimulates the secretion of insulin in a glucose-dependent
manner. Consequently, it may still be an appropriate agent for patients with relatively higher risk
The potential safety issue of heart failure risk that arose from SAVOR-TIMI 53 and the
Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care
(EXAMINE) trials led to the US FDA's recommendation  to consider discontinuing saxagliptin
and alogliptin for patients if heart failure develops. However, according to our meta-analysis,
risk of heart failure was similar with saxagliptin and comparators, with almost identical rates
of heart failure in both groups. The result was opposite to previous systematic reviews and
meta analyses, among which increased risk of heart failure was found in the treatment of
saxagliptin individually or DPP-4 inhibitors as an integrity. Until now, there is no identified
pathophysiology for the increased risk of heart failure by saxagliptin treatment. On the contrary,
previous preclinical and mechanistic studies of DPP-4 inhibitors suggest additional
nonglycemic beneficial actions on blood vessels and the heart, via both GLP-1-dependent and
GLP1-independent effects [
]. Positive effects of DPP-4 inhibitors on the myocardium have
also been described in patients with ischemic heart disease .
US FDA had warned that DPP-4 inhibitors may cause serious arthralgia in August 2015,
raising safety issues concerning the entire drug class and encouraging healthcare professionals
and patients to pay attention . In a search of the FDA Adverse Event Reporting System
database, FDA has identified 33 cases of serious arthralgia reported with the use of DPP-4
inhibitors between October 2006 and December 2013. However, the current finding from our
meta-analysis showed no safety signal for increased risk of arthralgia in the saxagliptin
treatment, and a possible better effect than sitagliptin. Furthermore, there was no increased risk of
pancreatitis and infections as supported by our studies, which was also consistent with
previous meta-analyses [59±62]. Postmarketing safety surveillance of saxagliptin will provide
further data on the incidences of adverse events.
In contrast to GLP-1 receptor agonists, saxagliptin does not mimic infused GLP-1 in its
effects on subjective satiety or gastric volume, which have been associated with noticeable
weight loss. Overall, saxagliptin appears to be associated with only modest changes in body
weight. In comparison with placebo, saxagliptin was associated with a slight gain in body
weight, which is of limited clinical significance. However, in comparison with sulfonylureas,
saxagliptin had a significant advantage on body weight (−2.34 kg).
In the US and Europe, saxagliptin has been approved for use in patients with type 2
diabetes, both as monotherapy and in combination with metformin, a sulfonylurea,
thiazolidinedione, or insulin, and also in combination with metformin plus insulin. However, in some
countries like China, it is currently only approved for use as monotherapy or in combination
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with metformin. Our systematic review has demonstrated significant advantages of saxagliptin
in achieving glycemic control when added to sulfonylureas, thiazolidinediones, or insulin,
with similar or better safety profiles. These results will help administrators in China and other
countries make evidence-based decisions.
This systematic review and meta-analysis of RCTs focused on the efficacy and safety of
saxagliptin in the treatment of T2D. The sample size of nearly 30,000 patients enabled the
demonstration of reliable results and the comparisons to most classes of oral antidiabetic drugs, by
which the knowledge around the comparative efficacy and safety was enriched. However,
there are some limitations in this study. Firstly, the follow-up periods of some included trials
were relatively short, which limited the observation of longtime outcomes among some
comparisons. Secondly, two trials included in the meta-analysis, which comparing saxagliptin with
vildagliptin, sitagliptin and (or) liraglutide, were found to have possible high risk of
performance and detection bias. This potential bias may reduce the credibility of corresponding
results. Interpretations of these findings must be made with caution. More head-to-head trials
between saxagliptin and active comparators are still needed to further confirm the efficacy and
safety of saxagliptin compared with other classes of antidiabetic drugs.
In conclusion, Generally, saxagliptin has similar efficacy compared with most oral
antidiabetic drugs, while may be more effective than acarbose. Saxagliptin is safe in the treatment of
T2D, especially having a better safety profile than acarbose and sulfonylureas.
S1 Text. PRISMA checklist.
S1 Fig. Risk of bias of included trials (a. graph; b. summary).
S2 Fig. Patients achieved HbA1c<7% (a. saxagliptin vs placebo; b. saxagliptin vs active
S3 Fig. Serious adverse events.
S4 Fig. Body weight (a. saxagliptin vs placebo; b. saxagliptin vs active comparators).
S5 Fig. Other adverse events [a. pancreatitis; b. heart failure; c. arthralgia (saxagliptin vs
placebo); d. arthralgia (saxagliptin vs active comparators); e. upper respiratory tract
infection (saxagliptin vs placebo); f. upper respiratory tract infection (saxagliptin vs active
comparators); g. urinary tract infection (saxagliptin vs placebo); h. urinary tract infection
(saxagliptin vs active comparators); i. nasopharyngitis (saxagliptin vs placebo); j.
nasopharyngitis (saxagliptin vs active comparators)].
Conceptualization: Peng Men, Hui-lin Tang, Suo-di Zhai.
Investigation: Peng Men.
Methodology: Peng Men, Hui-lin Tang.
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Project administration: Suo-di Zhai.
Writing ± original draft: Peng Men.
Writing ± review & editing: Xiao-tong Li, Suo-di Zhai.
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