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. 2022 Dec 30;17(12):e0279889. doi: 10.1371/journal.pone.0279889

Effect of SGLT-2 inhibitors on body composition in patients with type 2 diabetes mellitus: A meta-analysis of randomized controlled trials

Runzhou Pan 1, Yan Zhang 1, Rongrong Wang 1, Yao Xu 1, Hong Ji 1, Yongcai Zhao 1,*
Editor: Gulali Aktas2
PMCID: PMC9803203  PMID: 36584211

Abstract

Objective

Type 2 diabetes mellitus(T2DM) is closely related to sarcopenic obesity(SO). Body composition measurement including body weight, body mass index, waist circumference, percentage body fat, fat mass, muscle mass, visceral adipose tissue and subcutaneus adipose tissue, plays a key role in evaluating T2DM and SO. The weight reduction effect of sodium-glucose cotransporter 2(SGLT-2) inhibitors has been demonstrated. However, there are warnings that SGLT-2 inhibitors should be used with caution because they may increase the risk of sarcopenia. The effect of SGLT-2 inhibitors on body composition in T2DM is inconclusive. In this work, a meta-analysis of randomized controlled trials was conducted to evaluate the effect of SGLT-2 inhibitors on body composition in T2DM.

Methods

PubMed, the Cochrane Library, EMbase and Web of Science databases were searched by computer. All statistical analyses were carried out with Review Manager version 5. 3. Results were compared by weight mean difference(WMD), with 95% confidence intervals(CI) for continuous outcomes. A random effects model was applied regardless of heterogeneity. The I2 statistic was applied to evaluate the heterogeneity of studies. Publication bias was assessed using Funnel plots.

Results

18 studies with 1430 participants were eligible for the meta-analysis. SGLT-2 inhibitors significantly reduced body weight(WMD:-2. 73kg, 95%CI: -3. 32 to -2. 13, p<0. 00001), body mass index(WMD:-1. 13kg/m2, 95%CI: -1. 77 to -0. 50, p = 0. 0005), waist circumference(WMD:-2. 20cm, 95%CI: -3. 81 to -0. 58, p = 0. 008), visceral fat area(MD:-14. 79cm2, 95%CI: -24. 65 to -4. 93, p = 0. 003), subcutaneous fat area(WMD:-23. 27cm2, 95% CI:-46. 44 to -0. 11, P = 0. 05), fat mass(WMD:-1. 16kg, 95%CI: -2. 01 to -0. 31, p = 0. 008), percentage body fat(WMD:-1. 50%, 95%CI:-2. 12 to -0. 87, P<0. 00001), lean mass(WMD:-0. 76kg, 95%CI:-1. 53 to 0. 01, P = 0. 05) and skeletal muscle mass(WMD:-1. 01kg, 95%CI:-1. 91 to -0. 11, P = 0. 03).

Conclusion

SGLT-2 inhibitors improve body composition in T2DM including body weight, body mass index, waist circumference, visceral fat area, subcutaneous fat area, percentage body fat and fat mass reduction, but cause adverse effects of reducing muscle mass. Therefore, until more evidence is obtained to support that SGLT-2 inhibitors increase the risk of sarcopenia, not only the benefit on body composition, but also the adverse effect of the reduction in muscle mass by SGLT-2 inhibitors in T2DM should be considered.

Introduction

As one of the most serious and pressing health problems worldwide, type 2 diabetes mellitus (T2DM) is closely correlated with obesity, usually assessed by body mass index(BMI). However, BMI has crucial limitations due to its inability to assess weight distribution, fat mass and muscle mass. Fat accumulation and lean mass decrease are important changes that occur as adults age and are associated with an increased risk of T2DM [1]. T2DM is more closely related to fat distribution, percentage body fat and skeletal muscle than BMI [2]. Sarcopenic obesity (SO) is a new kind of complex syndrome characterized by double burden of sarcopenia (low muscle mass, muscle strength decreases and physical dysfunction) and excess fat [3]. T2DM is closely related to SO, and obesity is a common risk factor for both [4]. Body composition measurements include body weight, BMI, waist circumference, fat mass, percentage body fat, muscle mass, visceral adipose tissue and subcutaneus adipose tissue, which is performed by non-invasive techniques, playing a key role in evaluating T2DM and SO [5, 6].

As new class of oral hypoglycemic agents, sodium-glucose cotransporter 2(SGLT-2) inhibitors are paid attention due to unique mechanism of inhibiting proximal tubular glucose reabsorption and increasing urinary glucose excretion, which have been demonstrated to reduce body weight, improve cardiovascular and renal outcomes [7, 8]. However, there are warnings that SGLT-2 inhibitors should be used with caution due to the potential to increase the risk of dehydration and sarcopenia [9]. Therefore, the effect of SGLT-2 inhibitors on body composition in T2DM is worth discussing. This comprehensive systematic review and meta-analysis of randomized controlled trials (RCTs) aimed to evaluate the effects of SGLT-2 inhibitors on body composition in T2DM.

Materials and methods

Search strategy and study selection

PubMed, The Cochrane Library, EMbase and Web of Science databases were searched by computer. The combination of subject words and free words was used in the search. The search terms were as follows: (Sodium-Glucose Transporter 2 Inhibitors OR Ertugliflozin OR Dapagliflozin OR Canagliflozin OR Empagliflozin OR Ipragliflozin OR Luseogliflozin OR Tofogliflozin OR Sotagliflozin OR Gliflozins) AND (Body composition OR Waist circumference OR Skeletal muscle mass OR Fat mass OR Lean mass OR Visceral adipose tissue OR Subcutaneus adipose tissue), eligible search was limited to randomized controlled trials (RCTs). Two reviewers independently selected relevant articles based on their titles and abstracts, then screened the full text and resolved any differences by consensus with a third reviewer to determine whether it met the inclusion or exclusion criteria. All RCTs evaluating SGLT-2 inhibitors on body composition in T2DM were included in the meta-analysis. The following inclusive selection criteria were applied: (1)Participants were clinically diagnosed with T2DM. Patients with type 1 diabetes and gestational diabetes were excluded. There were no restrictions on the age, sex or race of participants. (2)The treatment group consisted of various types of SGLT-2 inhibitors, meanwhile the control group consisted of other hypoglycemic drugs. Both groups had sufficient baseline and post-treatment information in the study report, such as body weight(BW), BMI, waist circumference(WC), percentage body fat(PBF), fat mass(FM), lean mass(LM), skeletal muscle mass(SMM), visceral fat area(VFA) and subcutaneus fat area(SFA). (3)The study design was RCTs. Case reports, animal experiments, conference abstracts, reviews, subgroup analysis and editorials were excluded.

Data extraction and quality assessment

Two independent reviewers extracted the following information from eligible articles: first author, year of publication, sample size, type and dose of SGLT-2 inhibitors, control group medication, follow-up time and baseline patient information. Data collection for the following clinical outcomes: BW, BMI, FM, WC, PBF, LM, SMM, VFA and SFA. Two reviewers independently assessed the quality of RCTs using the Cochrane Risk of Bias tool, which includes the following seven criteria: random sequence generation (selection bias), allocation concealment(selection bias), blinding of participants and personnel(performance bias), blinding of outcome data(detection bias), incomplete outcome data(attrition bias), selective reporting(reporting bias)and other bias(certain biases not indicated above but influence the results). Each item was assessed as a "low risk", "high risk" or "unclear risk" of bias, according to recommendations in the Cochrane manual.

Statistical analysis

All statistical analyses were carried out with Review Manager version 5.3 Results compared by Weight mean difference (WMD), with 95% confidence intervals(CI) for continuous outcomes. The I2 statistic was used to assess study heterogeneity. Studies with I2 statistic of 25%-50% were characterized as low heterogeneity, I2 statistic of 50%-75% was characterized as moderate heterogeneity, I2 statistic higher than 75% was characterized as high heterogeneity. A random effects model was applied regardless of heterogeneity, followed by subgroup analysis or sensitivity analysis to explain the reason for heterogeneity as soon as possible. Publication bias was assessed using Funnel plots.

Results

Literature search

A total of 473 articles were selected by preliminary search, with 73 articles being duplications. 400 records were eliminated based on the titles and abstracts. 171 full text of potential studies were retrieved for further evaluations. 153 articles were excluded, including 109 non-RCT studies, 31 conference abstracts, 13 incomplete trial studies. Finally, 18 studies were eligible for the meta-analysis. The selection process is shown in Fig 1.

Fig 1. Flowchart of studies included in this meta-analysis.

Fig 1

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Basic characteristics and quality assessment

The characteristics of the 18 included studies published between 2013 and 2022 are shown in Table 1 [10–27]. The articles involved 1430 participants (726 SGLT-2 inhibitors participants and 704 control participants), including 7 multi-centre studies and 11 single-center studies. SGLT-2 inhibitors groups include canagliflozin (3 studies), dapagliflozin (8 studies), empagliflozin (3 studies) and ipragliflozin(4 studies), meanwhile control groups include traditional hypoglycemic drugs(16 studies), such as sulfonylureas, insulin, metformin, thiazolidinediones, DPP-4 inhibitors, etc and another new class of hypoglycemic drugs, GLP-1 receptor agonists(GLP-1RAs)(2 studies). 3 studies lasted 12 weeks, 10 studies lasted 24 weeks, 1 study lasted 26 weeks, 1 study lasted 28 weeks, 2 studies lasted 52 weeks and 1 study lasted 102 weeks. In addition, the Cochrane Risk Bias Assessment Tool was used to assess study bias. All studies were high-quality parallel grouped studies, and the quality assessment results of the included studies are summarized in S1 and S2 Figs.

Table 1. Demographic and clinical characteristics of included studies.

Author Country Year published Trial registration Agent Comparator SGLT-2 inhibitors(n) Control(n) Follow-up time
Bode B et al [10] 17 countries 2013 NCT01106651 Traditional hypoglycemic treatment+Canagliflozin Traditional hypoglycemic treatment+Placebo 71 74 26 weeks
Cefalu WT et al [11] 19 countries 2013 NCT00968812 Canagliflozin+Metformin Glimepiride+Metformin 102 96 52 weeks
Bolinder J et al [12] 5 countries 2014 NCT00855166 Dapagliflozin+Metformin Placebo+Metformin 69 71 102 weeks
Fadini GP et al [13] Italy 2017 NCT02327039 Traditional hypoglycemic treatment+Dapagliflozin Traditional hypoglycemic treatment+Placebo 15 16 12 weeks
Ito D et al [14] Japan 2017 UMIN000022651 Traditional hypoglycemic treatment+Iapagliflozin Traditional hypoglycemic treatment+Pioglitazone 32 34 24 weeks
Han E et al [15] Korea 2020 NCT02875821 Ipragliflozin+Metformin +Pioglitazone Metformin+Pioglitazone 29 15 24 weeks
McCrimmon RJ et al [16] 11 countries 2020 NCT03136484 Canagliflozin+Metformin Semaglutide+Metformin 23 22 52 weeks
Nakaguchi H et al [17] Japan 2020 UMIN000027614 Traditional hypoglycemic treatment+Empagliflozin Traditional hypoglycemic treatment+Liraglutide 31 30 24 weeks
Yamakage H et al [18] Japan 2020 UMIN000021479 Traditional hypoglycemic treatment+Dapagliflozin Traditional hypoglycemic treatment 26 24 24 weeks
Wolf VLW et al [19] Brazil 2021 NCT02919345 Dapagliflozin+Metformin Glibenclamide+
metformin		 44 45 12 weeks
Chehrehgosha H et al [20] Iran 2021 IRCT20190122042450N3 Empagliflozin Pioglitazone 35 34 24 weeks
Horibe K et al [21] Japan 2022 UMIN000020239 Traditional hypoglycemic treatment+Dapagliflozin Traditional hypoglycemic treatment 26 24 24 weeks
Inoue H et al [22] Japan 2019 UMIN000018839 Traditional hypoglycemic treatment+Ipragliflozin Traditional hypoglycemic treatment 24 24 24 weeks
Kayano H et al [23] Japan 2020 UMIN000023834 Traditional hypoglycemic treatment+Dapagliflozin Traditional hypoglycemic treatment 36 38 24 weeks
Kinoshita T et al [24] Japan 2020 UMIN000021291 Dapagliflozin Pioglitazone 32 33 28weeks
Tsurutani Y et al [25] Japan 2018 UMIN000014738 Traditional hypoglycemic treatment+Ipragliflozin Traditional hypoglycemic treatment 52 49 12 weeks
Shimizu M et al [26] Japan 2019 UMIN000022155 Traditional hypoglycemic treatment+Dapagliflozin Traditional hypoglycemic treatment 33 24 24 weeks
Zeng Y et al [27] Taiwan 2022 NCT03458715 Empagliflflozin+Premixed insulin Linagliptin+Premixed insulin 46 51 24 weeks
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Outcome meta-analysis

BW, BMI and WC

Fourteen RCTs reported BW in 617 SGLT-2 inhibitors users and 604 non-users. The meta-analysis showed that SGLT-2 inhibitors treatment significantly decreased BW compared with other drugs (WMD:-2. 73kg, 95%CI: -3. 32 to -2. 13, p<0. 00001). Low heterogeneity was found between studies (I2 = 33%). Seven RCTs reported BMI in 234 SGLT-2 inhibitors users and 219 non-users. In this meta-analysis, SGLT-2 inhibitors treatment significantly decreased BMI compared with other drugs (WMD:-1. 13kg/m2, 95%CI: -1. 77 to -0. 50, p = 0. 0005). No heterogeneity was observed between studies (I2 = 0%). Four studies evaluated the effects of SGLT-2 inhibitors on WC. Overall analysis showed that SGLT-2 inhibitors significantly reduced WC(WMD:-2. 20cm, 95%CI: -3. 81 to -0. 58, p = 0. 008). The I2 was 0%, showing that the result was stable (Fig 2).

Fig 2. Forest plots depicting BW, BMI and WC comparisons between SGLT-2 inhibitors and the control group.

Fig 2

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VFA and SFA

Eight studies of 429 participants showed that SGLT-2 inhibitors significantly decreased VFA compared with other antihyperglycemic drugs (MD:-14. 79cm2, 95%CI: -24. 65 to -4. 93, p = 0. 003), with no heterogeneous(I2 = 0). Six studies evaluated the effects of SGLT-2 inhibitors on SFA. Overall analysis showed that SGLT-2 inhibitors significantly decreased SFA (WMD:-23. 27cm2, 95% CI:-46. 44 to -0. 11, P = 0. 05), with no heterogeneity(I2 = 0) (Fig 3).

Fig 3. Forest plots depicting VFA and SFA comparisons between SGLT-2 inhibitors and the control group.

Fig 3

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FM, PBF, LM, SMM

Ten studies of 827 participants showed that SGLT-2 inhibitors significantly decreased FM compared with other antihyperglycemic drugs (WMD:-1. 16kg, 95%CI: -2. 01 to -0. 31, p = 0. 008), with a moderate heterogeneous(I2 = 65%). There were four studies that reported the effect of SGLT-2 inhibitors on PBF. In contrast with the control group, SGLT-2 inhibitors evidently reduced PBF (WMD:-1. 50%, 95%CI:-2. 12 to -0. 87, P<0. 00001), with no heterogeneity(I2 = 0%). Nine studies evaluated the effects of SGLT-2 inhibitors on LM. Overall analysis showed that SGLT-2 inhibitors significantly decreased LM compared with other antihyperglycemic drugs (WMD:-0. 76kg, 95%CI:-1. 53 to 0. 01, P = 0. 05). A moderate heterogeneity was found between studies (I2 = 74%). Seven studies in 206 SGLT-2 inhibitors users and 201 non-users evaluated the SMM. Overall analysis showed that SGLT-2 inhibitors significantly reduced SMM compared with other antihyperglycemic (WMD:-1. 01kg, 95%CI:-1. 91 to -0. 11, P = 0. 03), with no heterogeneity(I2 = 0) (Fig 4).

Fig 4. Forest plots depicting FM, PBF, LM and SMM comparisons between SGLT-2 inhibitors and the control group.

Fig 4

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Sensitivity analysis and subgroup analysis

In order to test heterogeneity, we did sensitivity analysis. When Nakaguchi and McCrimmon’s studies were removed, the heterogeneity decreased from 65% to 29% in the analysis of FM, with a decrease in P values (from 0. 008 to less than 0. 0001), and the heterogeneity decreased from 74% to 51% in the analysis of LM, with a decrease in P values (from 0. 05 to 0. 0001), so we further performed a subgroup analysis based on different control groups. The results showed that SGLT-2 inhibitors significantly reduced FM compared with traditional hypoglycemic treatment (WMD:-1. 74kg, 95%CI:-2. 32 to -1. 16, p<0. 00001). SGLT-2 inhibitors seemed to reduce FM less than GLP-1RAs, but there was no statistical difference (WMD:0. 71kg, 95%CI:-0. 55 to 1. 97, P = 0. 27) (S3 Fig). Compared with traditional hypoglycemic agents, SGLT-2 inhibitors significantly reduced LM (WMD:-1. 13kg, 95%CI:-1. 71 to -0. 56, P = 0. 0001). Compared with GLP-1RAs, SGLT-2 inhibitors seemed to decrease LM to a lower extent, but there was no statistical difference (WMD:0. 76kg, 95%CI:-0. 04 to 1. 56, P = 0. 06) (S4 Fig). Other outcomes, such as BW, BMI, WC, VFA, SFA and SMM were not carried out further tests due to low heterogeneity.

Discussion

This meta-analysis confirmed that SGLT-2 inhibitors reduced BW, BMI, WC, VFA, SFA, PBF, FM, LM and SMM to a greater extent than other hypoglycemic agents in T2DM.

Epidemiological evidence suggests that changes in body composition especially increased systemic FM and abdominal obesity, such as visceral adipose tissue, are strongly associated with T2DM risk [28]. BMI provides a fast and convenient standard for assessing obesity. However, the inability to specifically quantify total fat distribution, FM and LM has limited utility in estimating the risk of T2DM and other obesity-related diseases [29]. With similar BMI, LM decreased and FM increased more significantly in diabetic patients than in non-diabetic patients [30]. Studies have shown a strong relationship between T2DM and SO [4, 31], and body composition measurements are important tools for assessing both diseases [5, 6]. Bidirectional interactions have been hypothesized in obesity, low-grade inflammation, insulin resistance and sarcopenia [4]. Insulin in diabetic patients loses its function of promoting cellular glucose uptake and utilization, leading to insulin resistance, which destroys the role of insulin in inhibiting muscle protein breakdown, resulting in muscle fiber atrophy, muscle mass reduction and muscle strength decline [4]. On the contrary, SO may have synergistic effects with low-grade inflammation, which will increase production and secretion of various inflammatory factors and change insulin sensitivity by triggering different key steps of insulin signaling pathway, leading to insulin resistance and increasing risk of diabetes [32].

SGLT-2 inhibitors not only directly lead to weight loss through urinary glucose excretion mechanisms, but also improve adipocyte dysfunction in visceral adipose tissue, leading to leptin, visfatin, plasminogen activator inhibitor-1 decreased, adiponectin level increased, effectively promote lipolysis, reduce visceral fat [7, 33]. However, the unique mechanism of SGLT-2 inhibitors results in decreased insulin and elevated glucagon, limiting liver and muscle absorption of glucose and amino acids, promoting hepatic glucongenesis and glycogenolysis, and accelerating protein breakdown in muscle [9]. Case report of sarcopenia caused by SGLT-2 inhibitor use in elderly patients with T2DM has been published [34]. Therefore, it is critical to evaluate the effect of SGLT-2 inhibitors on body composition, such as fat distribution, fat mass and muscle mass in patients with T2DM.

As expected, the role of SGLT-2 inhibitors in body weight, WC, VFA and SFA reduction was confirmed in this meta-analysis, which was consistent with the conclusions of previous two meta-analyses [35, 36]. However, the previous two studies only targeted T2DM patients with non-alcoholic fatty liver disease, while this study targeted a wider range of T2DM patients, and the number of articles and subjects included was larger. In addition, this meta-analysis confirmed the advantages of SGLT-2 inhibitors in reducing FM and BFP, which had not been mentioned in previous meta-analyses. To sum up, these results suggest that SGLT-2 inhibitors may play an important role in improving body composition. Cefalu et al. confirmed that about two-thirds of the weight loss caused by SGLT-2 inhibitors was attributable to a reduction in FM, with the remaining third attributable to a reduction in LM [11]. Due to limited data, the proportion of weight loss from LM was not analyzed in this meta-analysis. However, according to the number of FM, LM and SMM decrease(-1. 74kg, -1. 13kg, -1. 01kg) comparing with other traditional hypoglycemic drugs, it can be inferred that the reduction of FM accounted for a greater proportion in weight loss of SGLT-2 inhibitors, which was roughly consistent with Cefalu’s conclusion. It should be noted that both LM and SMM play important roles in the diagnosis of sarcopenia and measurement of muscle mass [37]. LM measured with dual energy x-ray absorptiometry includes muscle, organs and body water, whereas bioelectrical impedance analysis measures SMM. This meta-analysis showed that SGLT-2 inhibitors significantly reduced both LM and SMM compared with other traditional hypoglycemic treatments, suggesting the adverse effects of SGLT-2 inhibitors on muscle mass decrease. In addition, the weight loss caused by SGLT-2 inhibitors may be due in part to body water loss, based on a unique glucose-lowering mechanism [38]. However, it should be noted that studies of ketosis and euglycemic ketoacidosis based on dehydration and insulinopenia during SGLT-2 inhibitors use have been reported [34, 39, 40]. Due to limited data, we did not conduct further analysis of water loss and risk of ketosis caused by SGLT-2 inhibitors. However, dehydration and ketosisis are also potential adverse effects that needs to be considered during SGLT-2 inhibitors use. In a word, despite producing a more favorable body composition, the potential of muscle mass loss induced by SGLT-2 inhibitors is noteworthy. Strategies to conserve skeletal muscle and improve physical function, such as through organized exercise, are important during the SGLT-2 inhibitors using.

Both GLP-1RAs and SGLT-2 inhibitors had favorable effects on BW. In this meta-analysis, the results showed that SGLT-2 inhibitors and GLP-1RAs had no significant difference in BW and FM loss. In addition, although there is no statistical difference in the LM reduction between the two drugs, the reduction by GLP-1RAs is more than that by SGLT-2 inhibitors. Therefore, the adverse effects of muscle mass reduction should be taken into account when the two drugs are used in patients with T2DM. However, this meta-analysis included only two studies comparing the body composition of the two drugs [16, 17]. More studies are needed to compare the difference in body composition changes between these two drugs.

The highlight of this meta-analysis is to confirm not only the advantages of SGLT-2 inhibitors in improving body composition, such as weight loss, BMI, WC, VFA, SFA, PBF and FM reduction, but also the adverse effects of these drugs on muscle mass reduction. However, the following are the limitations of this article:First, only a few RCTs met the conditions, and most of them had small sample sizes. Additional RCTs are needed to further validate the current results. Second, the included studies were followed up for a short period of time, with a median of 24 weeks, and the long-term effects of SGLT-2 inhibitors are unknown, so follow-up is needed. Third, due to the lack of data, the changes in the ratio of LM to FM and the changes in segmental LM were not analyzed. More research on the above parameters are needed to carry out in-depth discussions. Fourth, the studies included in the meta-analysis are from different ethnic groups, age ranges, genders and patient groups with comorbidities, and that there are many parameters that may affect muscle loss, suggesting that pre-planned prospective control and large-scale studies will be more instructive in this regard.

Conclusion

SGLT-2 inhibitors improve body composition in T2DM such as weight loss, BMI, WC, VFA, SFA, FM and PFM reduction, but cause adverse effects of reducing muscle mass. Therefore, until more evidence is obtained to support that SGLT-2 inhibitors increase the risk of sarcopenia, not only the benefit on body composition, but also the adverse effects of the reduction on muscle mass by SGLT-2 inhibitors in T2DM should be considered.

Supporting information

S1 Fig. Risk of bias graph.

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S2 Fig. Risk of bias summary.

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S3 Fig. Meta-analysis of FM level comparisons between SGLT-2 inhibitors and the control group based on the control.

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S4 Fig. Meta-analysis of LM level comparisons between SGLT-2 inhibitors and the control group based on the control.

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S1 Checklist. PRISMA 2009 checklist.

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Click here for additional data file. (171KB, pdf)

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

References

  • 1.Al-Sofiani ME, Ganji SS, Kalyani RR. Body composition changes in diabetes and aging. J Diabetes Complications. 2019. 33(6):451–459. doi: 10.1016/j.jdiacomp.2019.03.007 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Han TS, Al-Gindan YY, Govan L, Hankey CR, Lean MEJ. Associations of BMI, waist circumference, body fat, and skeletal muscle with type 2 diabetes in adults. Acta Diabetologica. 2019. 8(56):947–954. doi: 10.1007/s00592-019-01328-3 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Ji T, Li Y, Ma L. Sarcopenic Obesity: An Emerging Public Health Problem. Aging Dis. 2022. 13(2):379–388. doi: 10.14336/AD.2021.1006 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Wang M, Tan Y, Shi Y, Wang X, Liao Z, Wei P. Diabetes and Sarcopenic Obesity: Pathogenesis, Diagnosis, and Treatments. Front Endocrinol (Lausanne), 2020. 11:568. doi: 10.3389/fendo.2020.00568 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Lin C, Yu N, Wu H, Lee Y, Lin W, Chiu I, et al. Association of Body Composition with Type 2 Diabetes: A Retrospective Chart Review Study. Int J Environ Res Public Health. 2021. 18(9). 4421. doi: 10.3390/ijerph18094421 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Batsis JA, Villareal DT. Sarcopenic obesity in older adults: aetiology, epidemiology and treatment strategies. Nat Rev Endocrinol. 2018. 14(9): 513–537. doi: 10.1038/s41574-018-0062-9 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Pereira MJ, Eriksson JW. Emerging Role of SGLT-2 Inhibitors for the Treatment of Obesity. Drugs. 2019. 79(3): 219–230. doi: 10.1007/s40265-019-1057-0 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Palmer SC, Tendal B, Mustafa RA, Vandvik PO, Li S, Hao Q, et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1(GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ. 2021. 372: m4573. doi: 10.1136/bmj.m4573 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Yabe D, Nishikino R, Kaneko M, Iwasaki M, Seino Y. Short-term impacts of sodium/glucose co-transporter 2 inhibitors in Japanese clinical practice:considerations for their appropriate use to avoid serious adverse events. Expert Opin Drug Saf. 2015. 14(6):795–800. doi: 10.1517/14740338.2015.1034105 . [DOI] [PubMed] [Google Scholar]
  • 10.Bode B, Stenlöf K, Sullivan D, Fung A, Usiskin K. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract (1995). 2013. 41(2):72–84. doi: 10.3810/hp.2013.04.1020 . [DOI] [PubMed] [Google Scholar]
  • 11.Cefalu WT, Leiter LA, Yoon K, Arias P, Niskanen L, Xie J, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013. 382(9896): 941–50. doi: 10.1016/S0140-6736(13)60683-2 . [DOI] [PubMed] [Google Scholar]
  • 12.Bolinder J, Ljunggren Ö, Johansson L, Wilding J, Langkilde AM, Sjöström CD, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab. 2014. 16(2): 159–69. doi: 10.1111/dom.12189 . [DOI] [PubMed] [Google Scholar]
  • 13.Fadini GP, Bonora BM, Zatti G, Vitturi N, Iori E, Marescotti MC, et al. Effects of the SGLT2 inhibitor dapagliflozin on HDL cholesterol, particle size, and cholesterol efflux capacity in patients with type 2 diabetes: a randomized placebo-controlled trial. Cardiovasc Diabetol. 2017. 16(1): 42. doi: 10.1186/s12933-017-0529-3 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Ito D, Shimizu S, Inoue K, Saito D, Yanagisawa M, Inukai K, et al. Comparison of Ipragliflozin and Pioglitazone Effects on Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A Randomized, 24-Week, Open-Label, Active-Controlled Trial. Diabetes Care. 2017. 40(10): 1364–1372. doi: 10.2337/dc17-0518 . [DOI] [PubMed] [Google Scholar]
  • 15.Han E, Lee Y, Lee B, Kang ES, Cha BS. Ipragliflozin Additively Ameliorates Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Controlled with Metformin and Pioglitazone: A 24-Week Randomized Controlled Trial. J Clin Med. 2020. 9(1). 259. doi: 10.3390/jcm9010259 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.McCrimmon RJ, Catarig A, Frias JP, Lausvig NL, Roux CWI, Thielke D, et al. Effects of once-weekly semaglutide vs once-daily canagliflozin on body composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomised controlled clinical trial. Diabetologia. 2020. 63(3): 473–485. doi: 10.1007/s00125-019-05065-8 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Nakaguchi H, Kondo Y, Kyohara M, Konishi H, Oiwa K, Terauchi Y. Effects of liraglutide and empagliflozin added to insulin therapy in patients with type 2 diabetes: A randomized controlled study. J Diabetes Investig. 2020. 11(6): 1542–1550. doi: 10.1111/jdi.13270 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Yamakage H, Tanaka M, Inoue T, Odori S, Kusakabe T, Satoh-Asahara N. Effects of dapagliflozin on the serum levels of fibroblast growth factor 21 and myokines and muscle mass in Japanese patients with type 2 diabetes: A randomized, controlled trial. J Diabetes Investig. 2020. 11(3): 653–661. doi: 10.1111/jdi.13179 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Wolf VLW, Breder I, Carvalho LSF, Soares AAS, Cintra RM, Barreto J, et al. Dapagliflozin increases the lean-to total mass ratio in type 2 diabetes mellitus. Nutr Diabetes. 2021. 11(1): 17. doi: 10.1038/s41387-021-00160-5 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Chehrehgosha H, Sohrabi MR, Ismail-Beigi F, Malek M, Babaei MR, Zamani F, et al. Empagliflozin Improves Liver Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Diabetes Ther. 2021. 12(3): 843–861. doi: 10.1007/s13300-021-01011-3 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Horibe K, Morino K, Miyazawa I, Tanaka-Mizuno S, Kondo K, Sato D, et al. Metabolic changes induced by dapagliflozin, an SGLT2 inhibitor, in Japanese patients with type 2 diabetes treated by oral anti-diabetic agents: A randomized, clinical trial. Diabetes Res Clin Pract. 2022. 186: 109781. doi: 10.1016/j.diabres.2022.109781 . [DOI] [PubMed] [Google Scholar]
  • 22.Inoue H, Morino K, Ugi S, Tanaka-Mizuno S, Fuse K, Miyazawa I, et al. Ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, reduces bodyweight and fat mass, but not muscle mass, in Japanese type 2 diabetes patients treated with insulin: A randomized clinical trial. J Diabetes Investig. 2019. 10(4): 1012–1021. doi: 10.1111/jdi.12985 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Kayano H, Koba S, Hirano T, Matsui T, Fukuoka H, Tsuijita H, et al. Dapagliflozin Influences Ventricular Hemodynamics and Exercise-Induced Pulmonary Hypertension in Type 2 Diabetes Patients—A Randomized Controlled Trial. Circ J. 2020. 84(10): 1807–1817. doi: 10.1253/circj.CJ-20-0341 . [DOI] [PubMed] [Google Scholar]
  • 24.Kinoshita T, Shimoda M, Nakashima K, Fushimi Y, Hirata Y, Tanabe A, et al. Comparison of the effects of three kinds of glucose-lowering drugs on non-alcoholic fatty liver disease in patients with type 2 diabetes: A randomized, open-label, three-arm, active control study. J Diabetes Investig. 2020. 11(6): 1612–1622. doi: 10.1111/jdi.13279 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Tsurutani Y, Nakai K, Inoue K, Azuma K, Mukai S, Maruyama S, et al. Comparative study of the effects of ipragliflozin and sitagliptin on multiple metabolic variables in Japanese patients with type 2 diabetes: A multicentre, randomized, prospective, open-label, active-controlled study. Diabetes Obes Metab. 2018. 20(11): 2675–2679. doi: 10.1111/dom.13421 . [DOI] [PubMed] [Google Scholar]
  • 26.Shimizu M, Suzuki K, Kato K, Jojima T, Iijima T, Murohisa T, et al. Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease. Diabetes Obes Metab. 2019. 21(2): 285–292. doi: 10.1111/dom.13520 . [DOI] [PubMed] [Google Scholar]
  • 27.Zeng Y, Liu S, Lee C, Sun F, Liu JJ. Effect of empagliflozin versus linagliptin on body composition in Asian patients with type 2 diabetes treated with premixed insulin. Sci Rep. 2022. 12(1): 17065. doi: 10.1038/s41598-022-21486-9 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Preis SR, Massaro JM, Robins SJ, Hoffmann U, Vasan RS, Irlbeck T, et al. Abdominal subcutaneous and visceral adipose tissue and insulin resistance in the Framingham heart study. Obesity (Silver Spring). 2010. 18(11): 2191–8. doi: 10.1038/oby.2010.59 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Sneed NM, Morrison SA. Body Composition Methods in Adults with Type 2 Diabetes or at Risk for T2D: a Clinical Review. Curr Diab Rep. 2021. 21(5): 14. doi: 10.1007/s11892-021-01381-9 . [DOI] [PubMed] [Google Scholar]
  • 30.Kim TN, Park MS, Yang SJ, Yoo HJ, Kang HJ, Song W, et al. Prevalence and determinant factors of sarcopenia in patients with type 2 diabetes: the Korean Sarcopenic Obesity Study (KSOS). Diabetes Care. 2010. 33(7): 1497–9. doi: 10.2337/dc09-2310 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Khadra D, Itani L, Tannir H, Kreidieh D, Masri DE, Ghoch ME. Association between sarcopenic obesity and higher risk of type 2 diabetes in adults: A systematic review and meta-analysis. World J Diabetes. 2019. 10(5): 311–323. doi: 10.4239/wjd.v10.i5.311 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Bastard J, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw. 2006. 17(1): 4–12. . [PubMed] [Google Scholar]
  • 33.Sakurai S, Jojima T, Iijima T, Tomaru T, Usui I, Aso Y, et al. Empagliflozin decreases the plasma concentration of plasminogen activator inhibitor-1 (PAI-1) in patients with type 2 diabetes: Association with improvement of fibrinolysis. J Diabetes Complications. 2020. 34(11): 107703. doi: 10.1016/j.jdiacomp.2020.107703 . [DOI] [PubMed] [Google Scholar]
  • 34.Yasuda M, Iizuka K, Kato T, Liu Y, Takao K, Nonomura K, et al. Sodium-glucose cotransporter 2 inhibitor and sarcopenia in a lean elderly adult with type 2 diabetes: A case report. J Diabetes Investig. 2020. 11(3): 745–747. doi: 10.1111/jdi.13137 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Wong C, Yaow CYL, Ng CH, Chin YH, Low YF, Lim AYL, et al. Sodium-Glucose Co-Transporter 2 Inhibitors for Non-Alcoholic Fatty Liver Disease in Asian Patients With Type 2 Diabetes: A Meta-Analysis. Front Endocrinol (Lausanne). 2020. 11: 609135. doi: 10.3389/fendo.2020.609135 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Wei Q, Xu X, Guo L, Li J, Li L. Effect of SGLT2 Inhibitors on Type 2 Diabetes Mellitus With Non-Alcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials. Front Endocrinol (Lausanne). 2021. 12: 635556. doi: 10.3389/fendo.2021.635556 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Cruz-Jentoft AJ, Sayer AA. Sarcopenia. Lancet. 2019. 393(10191): 2636–2646. doi: 10.1016/S0140-6736(19)31138-9 . [DOI] [PubMed] [Google Scholar]
  • 38.Post A, Groothof D, Eisenga MF, Bakker SJL. Sodium-Glucose Cotransporter 2 Inhibitors and Kidney Outcomes: True Renoprotection, Loss of Muscle Mass or Both? J Clin Med. 2020. 9(5): 1603. doi: 10.3390/jcm9051603 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Bilgin S, Duman TT, Kurtkulagi O, Yilmaz F, Aktas G. A Case of Euglycemic Diabetic Ketoacidosis due to Empagliflozin Use in a Patient with Type 1 Diabetes Mellitus. J Coll Physicians Surg Pak. 2022. 32(7): 928–930. doi: 10.29271/jcpsp.2022.07.928 . [DOI] [PubMed] [Google Scholar]
  • 40.Bilgin S, Kurtkulagi O, Duman TT, Tel BMA, Kahveci G, Kiran M, et al. Sodium glucose co-transporter-2 inhibitor, Empagliflozin, is associated with significant reduction in weight, body mass index, fasting glucose, and A1c levels in Type 2 diabetic patients with established coronary heart disease: the SUPER GATE study. Ir J Med Sci. 2022. 191(4): 1647–1652. doi: 10.1007/s11845-021-02761-6 . [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Gulali Aktas

23 Nov 2022

PONE-D-22-30100Effect of SGLT-2 inhibitors on body composition in patients with type 2 diabetes mellitus: A meta-analysis of randomized controlled trialsPLOS ONE

Dear Dr. zhao,

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The paper is somewhat interesting but it should be improved according to the suggestions of the reviewers before further process.

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: Abstract is enough, The introduction is clear and explanatory. material method, statistics part is well explained and designed. The findings are beautifully and clearly written, both in writing and figures. In the literature, studies related to sglt2 have been scanned and discussed in a nice and detailed way. The discussion section could be expanded a bit though. You can benefit from the article mentioned in the journal below. I would also expect an important side effect such as euglycemic diabetic ketoacidosis to be mentioned in the discussion. In this respect, the article in the journal number 2 can be used.

1.Irish Journal of Medical Science (1971-), 191(4)

2.Journal of the College of Physicians and Surgeons--Pakistan: JCPSP, 32(7)

Reviewer #2: Dear author, the meta-analysis 'Effect of SGLT-2 inhibitors on body composition in patients with type 2 diabetes mellitus: A meta-analysis of randomized controlled trials' ;was evaluated. In this meta-analysis, the contribution of a group of drugs that are currently at the top of the preventive and therapeutic guidelines of all cardiovascular, diabetes and kidney diseases to muscle loss is evaluated.

I believe that it will contribute to the literature because it is a remarkable point.

Limitation: The fact that the studies included in the meta-analysis are from different ethnic groups, age ranges, genders and patient groups with comorbidities, and that there are many parameters that may affect muscle loss suggest that it is not appropriate to evaluate the results only for SGLT-2 treatment. Pre-planned prospective control and large-scale studies will be more instructive in this regard.

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Reviewer #1: No

Reviewer #2: Yes: Pinar Yildiz

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PLoS One. 2022 Dec 30;17(12):e0279889. doi: 10.1371/journal.pone.0279889.r002

Author response to Decision Letter 0

2 Dec 2022

Responses to the comments of Reviewer #1

I have accepted all your suggestions and add the following in the discussion section:In addition,the weight loss caused by SGLT-2 inhibitors may be due in part to body water loss,based on a unique glucose-lowering mechanism[38].However,it should be noted that studies of ketosis and euglycemic ketoacidosis based on dehydration and insulinopenia during SGLT-2 inhibitors use have been reported[34,39,40].Due to limited data,we did not conduct further analysis of water loss and risk of ketosis caused by SGLT-2 inhibitors.However,dehydration and ketosisis are also potential adverse effects that needs to be considered during SGLT-2 inhibitors use.

References

[38] Post A, Groothof D, Eisenga MF, Bakker SJL. Sodium-Glucose Cotransporter 2 Inhibitors and Kidney Outcomes: True Renoprotection, Loss of Muscle Mass or Both? J Clin Med.2020. 9(5): 1603. DOI: 10.3390/jcm9051603. PMID: 32466262.

[39] Bilgin S, Duman TT, Kurtkulagi O, Yilmaz F, Aktas G. A Case of Euglycemic Diabetic Ketoacidosis due to Empagliflozin Use in a Patient with Type 1 Diabetes Mellitus. J Coll Physicians Surg Pak. 2022. 32(7): 928-930. DOI: 10.29271/jcpsp.2022.07.928. PMID: 35795946.

[40] Bilgin S, Kurtkulagi O, Duman TT, Tel BMA, Kahveci G, Kiran M, et al. Sodium glucose co-transporter-2 inhibitor, Empagliflozin, is associated with significant reduction in weight, body mass index, fasting glucose, and A1c levels in Type 2 diabetic patients with established coronary heart disease: the SUPER GATE study. Ir J Med Sci. 2022. 191(4): 1647-1652. DOI: 10.1007/s11845-021-02761-6. PMID: 34476725.

Responses to the comments of Reviewer #2

I have accepted all your suggestions and add the following in the discussion section:Fourth,the studies included in the meta-analysis are from different ethnic groups, age ranges, genders and patient groups with comorbidities, and that there are many parameters that may affect muscle loss,suggesting that pre-planned prospective control and large-scale studies will be more instructive in this regard.

Attachment

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Click here for additional data file. (20.1KB, docx)

Decision Letter 1

Gulali Aktas

19 Dec 2022

Effect of SGLT-2 inhibitors on body composition in patients with type 2 diabetes mellitus: A meta-analysis of randomized controlled trials

PONE-D-22-30100R1

Dear Dr. zhao,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Gulali Aktas

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The manuacript is improved and reviewers suggest publication. I think the paper is acceptable, too. Well done.

Reviewers' comments:

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Comments to the Author

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Reviewer #1: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear authors

I reviewed your article again. Thank you for reviewing the journals I recommended and mentioning the topics that are suitable for your study.

**********

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Reviewer #1: No

**********

Acceptance letter

Gulali Aktas

21 Dec 2022

PONE-D-22-30100R1

Effect of SGLT-2 inhibitors on body composition in patients with type 2 diabetes mellitus: A meta-analysis of randomized controlled trials

Dear Dr. Zhao:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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Kind regards,

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on behalf of

Professor Gulali Aktas

Academic Editor

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Fig. Risk of bias graph.

    (TIF)

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    S2 Fig. Risk of bias summary.

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    S3 Fig. Meta-analysis of FM level comparisons between SGLT-2 inhibitors and the control group based on the control.

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    S4 Fig. Meta-analysis of LM level comparisons between SGLT-2 inhibitors and the control group based on the control.

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    S1 Checklist. PRISMA 2009 checklist.

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    Attachment

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    Data Availability Statement

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