Risk of urinary tract infection in patients with type 2 diabetes treated with dapagliflozin: A systematic review and meta-analysis of randomized controlled studies

DOI: https://doi.org/10.21203/rs.3.rs-1850015/v1

Abstract

As a selective inhibitor of sodium-glucose cotransporter 2, dapagliflozin is widely used in the treatment of type 2 diabetes mellitus (T2DM). However, whether it increases the risk of urinary tract infection (UTI) remains an ongoing issue. Therefore, we performed a systematic review and meta-analysis of randomized clinical trials (RCTs) to estimate the short-term and long-term risks of UTI in patients with T2DM who received dapagliflozin at different doses. As a selective inhibitor of sodium-glucose cotransporter 2, dapagliflozin is widely used in the treatment of type 2 diabetes mellitus (T2DM). However, whether it increases the risk of urinary tract infection (UTI) remains an ongoing issue. Therefore, we performed a systematic review and meta-analysis of randomized clinical trials (RCTs) to estimate the short-term and long-term risks of UTI in patients with T2DM who received dapagliflozin at different doses. We searched the PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov website from each database's inception to December 2021. The review protocol was previously registered in the PROSPERO database (CRD42022299899). A total of 40 RCTs involving 35573 patients were assessed for eligibility. The results showed that dapagliflozin imposed a higher risk of UTI compared to placebo and other active treatments, with a heterogeneity of 11% (OR 1.17, 95% CI 1.04-1.31, P=0.006). In the subgroup analysis, dapagliflozin 10 mg/d with a treatment period >24 weeks was associated with a significantly higher UTI risk than placebo or other active treatments (OR 1.27, 95% CI 1.13-1.43, P<0.0001). The ORs for dapagliflozin as monotherapy and combination therapy in the control group were 1.05 (95% CI 0.88-1.25, P=0.571) and 1.27 (95% CI 1.09-1.48, P=0.008), respectively. Overall, dapagliflozin 10 mg daily with a treatment duration of more than 24 weeks may significantly increase the risk of UTI in patients with T2DM. The combination of dapagliflozin and other glucose-lowering drugs might be associated with a higher risk of UTI. Therefore, high-dose, long-term treatment and add-on therapy of dapagliflozin call for careful consideration of the risk of UTI in T2DM patients.

Introduction

Due to the progressive nature of T2DM, the goal of durable glycemic control to decrease the risks of various morbidities and mortalities remains a challenge in the management of patients with the disease. Despite the use of combination therapies, many patients fail to achieve optimal glycaemic targets with a low risk of side effects over time. Therefore, an ideal add-on oral antidiabetic agent with long-term efficacy and tolerability is still currently in demand.

Dapagliflozin is a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2) that augments urinary glucose excretion in the proximal tubule of the kidney, and thereby reduces plasma glucose regardless of insulin sensitivity and β-cell secretory function. In addition, this effect of glucosuria is also associated with weight loss via caloric elimination and reduced blood pressure related to osmotic diuresis. The effect depends on baseline glycaemic control and the renal filtration rate but is independent of insulin.

Since the clinical use of dapagliflozin therapy should be based on a balance of efficacy and safety, a solid understanding of the drug’s safety profile of it is of critical importance. Recently, several studies have confirmed an association between the high risk of genital infection and the use of dapagliflozin in T2DM patients1,2. However, the controversy over the association of UTI risk and dapagliflozin use remains due to the different outcomes of previous studies. Several clinical studies have concluded that dapagliflozin significantly increased the risk of UTI in T2DM patients36. In contrast, some other RCTs didn’t find any significant correlation between dapagliflozin use and UTI79. Furthermore, the conclusions of various of meta-analyses were also contradictory1014. Nonetheless, most of conclusions were less convincing owing to the small quantity of included studies with insufficient statistical power, high heterogeneity in study design, short-term study duration or potential publication bias. Li et al.15 conducted a systematic review of 52 RCTs assessing different types of SGLT2 inhibitors and found that only dapagliflozin had a dose-response relationship with UTI. However, the difference between the short-term and long-term risks of UTI associated with dapagliflozin use was not elucidated in that study.

Because the relationship between dapagliflozin use and UTI warrants further discussion, we conducted a systematic review and meta-analysis of studies to estimate the short-term and long-term risks of UTI over a follow-up period of ≥ 12 weeks in patients with T2DM who received dapagliflozin at three different dosages. The influence of dapagliflozin on the risk of UTI when used as an add-on treatment and as a monotherapy was also analysed.

Methods

Data sources and search strategy

The systematic review and meta-analysis were performed and reported according to the

Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 statement16 (Table S1). The review protocol was previously registered in the PROSPERO database (CRD42022299899). We searched the PubMed, EMBASE, and the Cochrane Library from each database's inception to December 2021; languages restricted to English and Chinese, and we used both Medical Subject Heading (MeSH) and free text terms. The ClinicalTrials.gov website was also searched for RCTs that were registered as completed but unpublished. A manual search of the bibliographies of the retrieved articles was conducted to supplement the search results. Two investigators (Dongyuan He and Jianguo Chen) independently screened the titles and abstracts and reviewed the full texts of potentially relevant studies for eligibility. Any disagreements regarding the identification of eligible studies were resolved by discussion with a third author. The detailed search strategy is provided in Table S2.

Study Selection

We sought RCTs with a duration of at least 12 weeks that were conducted with adult patients (aged 18 to 80 years) who had been diagnosed with T2DM based on the World Health Organization criteria. Only studies published in English and Chinese that compared dapagliflozin (as a monotherapy or an add-on therapy) with placebo or other glucose-lowering drugs were included. Reviews, observational studies, case reports, retrospective studies, letters to the editors, and conference abstracts were excluded. Trials that were non randomized were not double-blinded, lasted less than 12 weeks, included patients with type 1 diabetes, had a lack of adverse events, or those that involved nonhuman species were also excluded. If multiple publications for one particular RCT existed, we extracted data from the publication with the longest follow-up duration.

Data extraction and quality assessment

Two investigators (Xiaohui Xie and Yunan Lu) independently extracted the following data from each study using a standardized tool: first author, publication year, country, study design, randomization method, participant characteristics (number, sex, age, BMI, duration of diabetes, HbA1c), outcome measures, and follow-up duration. The quality of the studies was independently assessed for risk of bias by two authors (Zhigui Zheng and Xinxin Jiang) using the Cochrane Collaboration Risk of Bias Assessment Tool. The following items were assessed: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias. Each domain was graded as having a low risk of bias, an unclear risk of bias or a high risk of bias. Only the manuscript with largest sample size or longest duration was chosen if an RCT had been published in multiple journals.

Data synthesis and analysis

The main outcome was the prevalence of UTI in the dapagliflozin group and in the control group. The corresponding odds ratios were calculated based on the original data.I 2 test was used to assess the statistical heterogeneity of the included studies. Values of 0-0.25, 0.26-0.50, 0.51-0.75 and >75% represented insignificant, low, moderate and high heterogeneity, respectively. If the overall heterogeneity was at a moderate or high level, a random-effects model was used; otherwise, a fixed-effects model was used. Subgroup analysis was also performed to reduce heterogeneity based on the treatment duration or the method of dapagliflozin administration(monotherapy/combination therapy). We generated Egger’s regression test and funnel plots to assess the publication bias. The strength of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach (https://gdt.gradepro.org/app). In addition, sensitivity analyses were conducted by removing each study sequentially to ascertain the robustness of the results. The statistical analyses was performed using STATA 15.0 (Stata, College Station, TeXas, USA). All tests were 2-tailed, and P<0.05 was considered to indicate statistical significance.

Results

Search results and study characteristics

The flow chart of the selection process is presented in Figure.1. We initially identified 268 studies according to the search strategy previously described. Finally, a total of 40 RCTs were included after screening the abstracts and full-texts of the articles for eligibility3-9,17-48. The characteristics of the retrieved trials and the demographic data of the participants are summarized in Table 1.The trials were published between 2008 and 2021 and involved a total of 35573 participants. The median follow-up duration ranged from 12 to 218 weeks, the mean ages of the patients were 59.9-68 years and 16977 participants (47.72%) were female. The mean baseline HbA1c ranged from 5.6% to 9.2%, and the mean baseline BMI ranged from 25.1 to 33.1 kg/m2. All except one trial were multicentre studies30. There were 6633(34.39%) patients who used dapagliflozin as an add-on therapy in the experimental group. In the control group, 4927(30.42%) patients were treated with other glucose-lowering drugs or their combination, including metformin, sitagliptin, glimepiride, glipizide, saxagliptin, exenatide, pioglitazone and insulin. One study was open-labelled45. In the study by Ferrannini et al.46, we merged the data of the participants who received dapagliflozin at the same dosage in the morning or in the evening. We also combined the data of two treatment arms that included participants of different ages in another clinical trial3. Patients received dapagliflozin twice a day in the study by Schumm-Draeger et al.37 and the total daily dose was calculated. There were two independent studies included in one study conducted by Henry et al.23, the data of which were separately analysed according to the research method.

Risk of bias and sensitivity analysis

According to the Cochrane Collaboration’s tool used for the overall quality assessment, all trials demonstrated a low risk of bias. The risk of bias was high or unclear for random sequence generation in 10 trials (26.3%), allocation concealment in 21 trials (55.3%), blinding of participants and personnel in 7 trials (18.4%), blinding of outcome assessment in 8 trials (21.1%), and selective reporting in 12 trials (31.6%) (Figure S1A and S1B). The funnel plots were visually symmetric and Egger’s test did not suggest any evidence of significant publication bias (Figures S2A-S2C). Sensitivity analyses demonstrated that the odds ratios did not find significant changes when removing one study at a time, thus confirming the robustness of the results. The GRADE evaluation indicated that the main outcomes had high quality of the evidence(Table S3).

Primary analysis

The pooled prevalence of UTI was 4.09% (95%CI: 2.21-6.48%) in the dapagliflozin group and 3.46% (95% CI: 1.65-5.78%) in the control group. In the meta-analysis of all 40 RCTs, dapagliflozin imposed a higher risk of UTI compared to placebo and other active treatments, with a heterogeneity of 11% (OR 1.17, 95% CI 1.04-1.31, P=0.006).

Subgroup analysis 

Figures 2-4 show the results of the meta-analysis at different dosages of dapagliflozin stratified by duration (≤24 weeks vs. >24 weeks). There was apparently no statistically significant difference in the incidence of UTI between participants who received dapagliflozin 5 mg and control group participants (OR=1.16, 95% CI: 0.90-1.49, P=0.15) or between participants who received dapagliflozin 2.5 mg per day and control group participants (OR=0.92, 95% CI: 0.59-1.45, P=0.73), regardless of the two different treatment durations. No significant difference was detected between the participants who received dapagliflozin 10 mg daily and control group participants when the treatment period was ≤ 24 weeks (OR 1.32, 95% CI 1.00-1.74, P=0.05). However, dapagliflozin 10 mg/d with a treatment period >24 weeks was associated with a significantly higher UTI risk than placebo or other active treatments (OR 1.26, 95% CI 1.10-1.44, P=0.001).  

Subgroup analysis stratified by two different interventions in the dapagliflozin group (monotherapy or combination with other active treatments) was also implemented, and the pooled ORs for monotherapy and combination therapy were 1.05 (95% CI 0.88-1.25, P=0.571) and 1.27 (95% CI 1.09-1.48, P=0.002), respectively (Figure 5). The results indicated that dapagliflozin combined with other glucose-lowering drugs may increase the risk of UTI.

Discussion

Our meta-analysis of 40 randomized, controlled clinical trials found that dapagliflozin was associated with more frequent UTI compared with placebo and other active treatments. With respect to the effects of different dosage, a significantly increased risk of UTI was only identified with dapagliflozin 10 mg daily. We also confirmed the influence of different treatment durations of dapagliflozin on UTI occurrence at three levels of dosage in a subgroup analysis. The findings suggest that UTI is more common among patients treated with dapagliflozin 10 mg daily than among those receiving placebo and active therapy in treatment periods of more than 24 weeks. To our knowledge, this is the first meta-analysis to substantially expand on the data involving long-term treatment of dapagliflozin in patients with T2DM based on the current evidence.

Recent studies have still failed to reach a consensus on whether dapagliflozin exerts an influence on the risk of UTI3,4,7,8. According to its therapeutic mechanism, dapagliflozin induces glycosuria by inhibiting the urinary reabsorption of glucose, which is considered as a reasonable risk factor for UTI. Nonetheless, findings in patients with familial renal glucosuria are contrary to the hypothesis that it may not contribute to the increased incidence of UTI49. Furthermore, it has been verified that hyperglycaemia is significantly related to impaired immune system impairment50, which may increase the risk of diverse infectious events including UTI. Therefore, antihyperglycaemic therapy with dapagliflozin could theoretically reduce the prevalence of UTI. However, our findings reconfirms the results of some previous studies demonstrating that high-dose dapagliflozin is associated with an increased risk of UTI1,11,13,15. There are two possible reasons for these contradictory conclusions. First, several previous meta-analyses were limited by a relatively small number of RCTs with insufficient statistical power to detect the clinically important side effects. Second, the heterogeneity in the design of clinical trials among the included RCTs may also have affected the final conclusions. We augmented many updated RCTs and performed the subgroup analysis based on the elements of experimental design, which made the result more convincing.

Even though the relationships between two low-dose levels of dapagliflozin and the risk of UTI were not confirmed, our meta-analysis findings suggested that the risk still exhibited a dose-related trend (including the 10 mg daily dose). This is consistent with another meta-analysis conducted by Puckrin et al.1, which compared only two different dosing regimens. However, Musso et al.13 found that the risk of UTI was not dose-related. Several confounding variables may account for this, such as different sample sizes, publication bias originating from the diagnosis criteria of UTI and the influence of differences in the intervention measures in the control group.

Moreover, we realize that the combination therapy of dapagliflozin and other The importance of this aspect has not been highlighted in the limited published trials. In the study by Rosenstock et al.24, it was reported that UTI was more common in dual add-on therapy than in triple therapy, both of which included dapagliflozin. In contrast, another study demonstrated that the frequencies of UTI were slightly higher with triple therapy than with dual therapy in both men and women43. However, in addition to their conflicting results, neither of the studies compared the incidences of UTI between single-agent therapy of dapagliflozin and combination therapy. Based on a certain number of RCTs, we performed a stratified analysis to compare the risk of UTI between the abovementioned two treatment modes, which could generate relatively objective results. To date, there are no relevant clinical data that address this. Our findings demonstrate that administering dapagliflozin as an add-on therapy in the treatment of patients with T2DM calls for the careful consideration of the higher risk of UTI compared to its use as a monotherapy. The precise underlying mechanism is unknown. It may be related to the inadequacy of reaching glycaemic targets in those patients who required add-on therapy. This warrants further investigation in the future.

Based on prior studies, most UTI events were reported to be of mild or moderate intensity. They responded to standard antimicrobial treatment, and rarely led to an interruption of dapagliflozin therapy28,51,52. Only a small minority of infections develop into pyelonephritis or urosepsis1,28,53. Although a few studies have observed a greater rate of recurrence of UTI with dapagliflozin compared with placebo51,54, most of the infections were single episodes and rarely led to recurrence. It is also widely accepted that the clinical diagnosis of UTI occurs more frequently in women than in men. We did not conduct further research on the abovementioned clinical aspects, which were either established facts or lacked data.

As previously mentioned, our study has several advantages. First, the main strength of the review is that all the conclusions are based on a much larger number of RCTs with different durations of follow-up. In several published meta-analyses, the most common limitation was the small quantity of included trials with a short duration10,11,13. Second, although the systematic review by Puckrin et al.1 included a longer period of follow-up time, a difference in the risks of UTI between short-term and long-term treatment with dapagliflozin was not observed. Our study indicated that the risk of UTI may not increase even at a dose of 10 mg/d if the treatment duration is less than 24 weeks. Third, it was also observed that a combination therapy of dapagliflozin and another hypoglycaemia agent in T2DM patients may induce a higher risk of UTI, although few data are available. Moreover, the study was performed using a prespecified protocol in line with PRISMA guidelines, and the included studies were assessed with the Cochrane Collaboration’s tool.

The limitations of our study should be acknowledged. First, we decided to combine data that compared dapagliflozin with placebo or other active comparators in one set of analyses according to the heterogeneity in the clinical study design. The different effects on the risk of UTI among hypoglycaemic agents other than dapagliflozin cannot be completely ruled out. Second, we didn’t implement the subgroup analysis stratified by age because of the paucity of original data. The distinction of risk of UTI due to age among the RCTs may exist. Third, we only focused on the influences of three dose of dapagliflozin, and more unconventional doses including 2.5 mg/d and 20 mg/d were not analysed. Fourth, the diagnostic criteria of UTI varied from the presence of signs and symptoms in the reporting methods to specific laboratory testing. We combined the data in order to facilitate the analysis, which could be a potential confounder.

Conclusion

In summary, the results of our analysis showed an increased risk of UTI associated with dapagliflozin 10 mg daily but not with dapagliflozin 5 mg daily or dapagliflozin 2.5 mg daily, especially for patients with a treatment period of more than 24 weeks. The combination therapy of dapagliflozin and other hypoglycaemic agents may also lead to a higher risk of UTI than a single treatment. Hence, careful monitoring for UTI is still recommended during the administration of dapagliflozin at a high dose or as an add-on therapy for long-term treatment.

Declarations

Data availability

All data generated or analysed during this study are included in this published article [and its supplementary information files].

Acknowledgements

Not applicable.

Author contributions

Z.G. contributed to conception and design, analysis, and wrote the manuscript. X.X. contributed to conception and design, interpretation of data, and the revision of the draft. D.Y. contributed to statistical analysis of the data, and review/editing of the manuscript. J.G. contributed to study design, data collection and analysis. X.H. and Y.N. participated in data collection and interpretation. B.B. participated in design of the study, and reviewed/edited the manuscript.

Funding

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Tables

Table 1. Characteristics of included studies.

Author

Year

Design

Interventions

N

Age

(years)

Female

(n(%))

HbA1C(%)

BMI(kg/m2)

Duration of
 diabetes(years)

Follow-up  periods

(weeks)

Wiviott7

2019

multi-centre RCT

DAPA 10 mg/d

8582

63.9±6.8

5411(63.1)

8.3±1.2

32.1±6.0

11.0(6.0-16.0)

218

PBO

8578

64.0±6.8

3251 (37.9)

8.3±1.2

32.0±6.1

10.0(6.0-16.0)

Fioretto17

2018

multi-centre RCT

DAPA 10 mg/d

160

65.3

69 (43.1)

8.03±1.08

32.6±4.7

14.3±8.0

24

PBO

161

66.2

70 (43.5)

8.33±1.08

31.6±5.0

14.5±8.3

Heerspink18

2013

multi-centre RCT

DAPA 10 mg/d

24

53.7±9.4

8(33.3)

7.7±0.6

NR

6.5±4.4

12

PBO

25

58.0±9.5

7(28)

7.5±1.0

NR

6.5±5.0

 Bailey19

2010

multi-centre RCT

DAPA 2.5 mg/d

137

55.0±9.3

67(49)

7.99±0.9

31.6±4.8

6.0±6.2

24

DAPA 5 mg/d

137

54.3±9.4

68(50)

8.17±0.96

31.4±5.0

6.4±5.8

DAPA 10 mg/d

135

52.7±9.9

58(43)

7.92±0.82

31.2±5.1

6.1±5.4

PBO

137

53.7±10.3

61(45)

8.11±0.96

31.8±5.3

5.8±5.1

Wieland6

2018

multi-centre RCT

DAPA 10 mg/d+MET

314

57.4±9.4

112 (35.7) 

8.3±0.7 

33.1±5.2

6.9±5.2

52

GLIM+MET

313

58.6±8.4

105 (33.5) 

8.3±0.8

33.0±5.1

6.7±5.1

Pollock20

2019

multi-centre RCT

DAPA 10 mg/d

145

64.7±8.6

43(30) 

8.44±1.0

30.19±5.3

17.55±7.7

24

PBO

148

64.7±8.5

43(29) 

8.57±1.2

30.34±5.6

17.71±9.5

Cefalu9

2015

multi-centre RCT

DAPA 10 mg/d

455

62.8±7.0

146(32.1)

8.18±0.84

32.6±5.9

12.6±8.6

52

PBO

459

63.0±7.7

144(31.4) 

8.08±0.80

32.9±6.1

12.3±8.2

Bolinder21

2014

multi-centre RCT

DAPA 10 mg/d+MET

91

60.6±8.2

40(44.0)

7.19±0.44

32.1±3.9

6.0±4.5

102

MET+PBO

91

60.8±6.9

40(44.0)

7.16±0.53

31.7±3.9 

5.5±5.3

Kohan22

2014

multi-centre RCT

DAPA 5 mg/d

83

66±8.9

28(33.7)

8.30±1.04

NR

16.9±9.0 

104

DAPA 10 mg/d

85

68±7.7

29(34.1)

8.22±0.98

NR

18.2±10.1

PBO

84

67±8.6

31(36.9)

8.53±1.28

NR

15.7±9.5

Henry23

2012

multi-centre RCT

DAPA 5 mg/d+PBO

203

52.3±10.2

111 (54.7) 

9.1±1.4

NR

1.6±3.1

24

DAPA 5 mg/d+MET

194

51.7±9.3

116(59.8) 

9.2±1.3

NR

1.6±2.4

MET+PBO

201

51.8±9.8

106(52.7) 

9.2±1.3

NR

1.6±2.6

Henry23

2012

multi-centre RCT

DAPA 10 mg/d+PBO

219

51.1±11.5 

114(52.1) 

9.1±1.3 

NR

2.1±3.8

24

DAPA 10 mg/d+MET

211

51.0±10.1

105(49.8)

9.1±1.3 

NR

2.2±3.3

MET+PBO

208

52.7±10.4

111(53.4)

9.1±1.3 

NR

1.9±4.0

Stefano5 

2015

multi-centre RCT

DAPA 10 mg/d+MET

400

58.1±9.4

179(44.7)

7.69±0.86

31.7±5.1

6.1±4.6

208

GLIP+MET

401

58.6±9.8

181(45.1)

7.74±0.89

31.2±5.1

6.6±5.9

 Rosenstock24

2015

multi-centre RCT

SAXA+DAPA 10 mg/d+MET

179

53±10

94(53) 

8.92±1.18 

31.8±4.8 

7.1±5.0 

24

SAXA+MET

176

53±10

82(47)

9.03±1.05 

31.8±5.1

8.2±5.5 

DAPA 10 mg/d+MET

179

54±10

90(50)

8.87±1.16

31.5±5.3

7.4±5.4 

James25

2009

multi-centre RCT

DAPA 2.5 mg/d

53

55±11

30(51)

7.6±0.7

32±5 

NR

12

DAPA 5 mg/d

55

55±12

30(52)

8.0±0.9

32±5

NR

DAPA 10 mg/d

40

54±9

22(47)

8.0±0.8 

31±5 

NR

PBO

44

53±11 

24(44)

7.9±0.9

32±5 

NR

Bailey26

2013

multi-centre RCT

DAPA 2.5 mg/d+MET

137

55±9.3

67(49)

7.99±0.9

31.6±4.8

6.0±6.2

102

DAPA 5 mg/d+MET

137

54.3±9.4

68(50)

8.17±0.96

31.4±5.0

6.4±5.8

DAPA 10 mg/d+MET

135

52.7±9.9

58(43)

7.92±0.82

31.2±5.1

6.1±5.4

PBO+MET

137

53.7±10.3 

61(45)

8.11±0.96

31.8±5.3

5.8±5.1

Jabbour27

2014

multi-centre RCT

DAPA 10 mg/d 

223

54.8±10.4 

96(43)

7.9±0.8

NR

5.7±4.87

48

PBO

224

55.0±10.2 

106(47.3) 

8.0±0.8 

NR

5.64±5.4 

Wilding28

2014

multi-centre RCT

PBO+INS

197

58.8±8.6 

98(50.8)

8.47±0.77 

33.1±5.9

13.5±7.3

104

DAPA 2.5 mg/d+INS

202

59.8±7.6 

102(50.5)

8.46±0.78 

33.0±5.0

13.6±6.6

DAPA 5 mg/d+INS

212

59.3±7.9 

111(52.6)

8.62±0.89 

33.0±5.3

13.1±7.8

DAPA 10 mg/d+INS

196

59.3±8.8

107(55.2)

8.57±0.82

33.4±5.1

14.2±7.3

Ji29

2014

multi-centre RCT

DAPA 5 mg/d

128

53±11.07

44(34.4)

8.14±0.74

25.17±3.29

1.15±2.3

24

DAPA 10 mg/d

133

51.2±9.89

47(35.3)

8.28±0.95

25.76±3.43

1.67±2.8

PBO

132

49.9±10.87

45(34.1)

8.35±0.95

25.93±3.64

1.3±2.0

Fadini30

2017

single-centre RCT

DAPA 10mg/d

15

66.3±1.8

5(33.3)

8.2±0.2

28.4±1.4

14.2±1.3

12

PBO

16

61.0±1.8 

6(37.5)

8.2±0.2

32.8±1.4

13.9±1.3 

Rosenstock31

2019

multi-centre RCT

DAPA 5 mg/d+SAXA+MET

290

57.2±10.7 

148(51.0) 

8.1±0.9 

31.5±5.5 

7.5±6.3 

24

DAPA 5 mg/d+MET

289

55.9±10.9 

137(47.4) 

8.2±0.9 

31.8±5.2 

7.6±6.3 

SAXA+MET

291

57.0±9.9

134(46.0) 

8.3±1.0 

32.4±5.5

7.8±5.8

Yang32

2017

multi-centre RCT

PBO

497

54.3±10.7

208(41.9)

8.18±0.98

25.7±3.7

4.2±4.9

24

DAPA 5 mg/d

491

55.1±10.2

215(44.2)

8.10±0.9

25.4±3.4

3.8±4.5

DAPA 10 mg/d

465

54.7±10

179(42.4)

8.08±0.88

26.1±3.9

4.4±4.5

Rosenstock33

2012

multi-centre RCT

PBO+PIOG

139

53.5±11.4

68(48.9) 

8.34±1.00 

NR

5.07±5.05

48

DAPA 5 mg/d+PIOG

141

53.2±10.9

63(44.7) 

8.40±1.03

NR

5.64±5.36

DAPA 10 mg/d+PIOG

140

53.8±10.4

81(57.9)

8.37±0.96

NR

5.75±6.44

Matthaei34

2015

multi-centre RCT

DAPA 10 mg/d

108

61.1±9.7

62(57.4)

8.08±0.91

31.9±4.8

9.3±6.5

24

PBO

108

60.9±9.2

48(44.4) 

8.24±0.87

32.0±4.6

9.6±6.2

Bailey35

2012

multi-centre RCT

PBO

68

53.5±11.08

31(45.6)

7.8±1.12

32.47±4.91

1.1±1.95

24

DAPA 2.5 mg/d 

74

53.5±10.61

40(54.1)

8.1±1.07

31.13±5.47

1.5±2.19 

DAPA 5 mg/d

68

51.3±11.51

32(47.1)

7.9±1.03

30.97±5.68

1.4±3.24

Weber36

2016

multi-centre RCT

PBO

311

56.2±8.9 

140(45.0) 

8.0±0.9 

NR

7.6±6.2

12

DAPA 10 mg/d

302

55.6±8.4

179(59.3)

8.1±1.0

NR

8.2±6.4

Schumm-Draeger37

2015

multi-centre RCT

PBO+MET

101

58.5±9.4

54(53.5)

7.94±0.85

31.74±4.69

5.53±4.23

16

DAPA 5 mg/d+MET

100

55.3±9.3

63 (63.0) 

7.77±0.75

33.16±5.16

4.80±3.87

DAPA 10 mg/d+MET 

99

58.5±9.8

53 (53.5) 

7.78±0.76

33.09±4.94

5.12±4.2

Araki38

2016

multi-centre RCT

PBO+INS

60

57.6±9.86

20 (33.3)

8.52±0.94

26.12±3.49

8.33±7.53

52

DAPA 5 mg/d+INS

122

58.3±9.83

89 (73.0)

8.26±0.79

26.89±4.93

6.01±4.70

Leiter3

2014

multi-centre RCT

PBO+INS

482

63.6±7.0 

159 (33.0)

8.1±0.8 

32.7±5.7

13.0±8.4

52

DAPA 10 mg/d+INS

480

63.9±7.6

159 (33.1)

8.0±0.8

33.0±5.3

13.5±8.2

Kaku39

2014

multi-centre RCT

PBO

87

60.4±9.7

35(40.2)

7.5±0.63

25.22±4.39

5.29±6.17

24

DAPA 5 mg/d

86

58.6±10.4

36(41.9)

7.5±0.72

24.88±3.91

4.59±5.56

DAPA 10 mg/d

88

57.5±9.3

35(39.8)

7.46±0.61

26.06±4.52

4.93±4.52

Mathieu40

2016

multi-centre 

RCT

PBO+MET+SAXA 

160

55±9.6

84(52.5)

8.17±0.98

32.2±5.3

8.0±6.6

52

DAPA 10 mg/d+MET+SAXA

160

 

55.2±8.6

90(56.3)

8.24±0.97

31.2±4.7

7.2±5.7

Strojek8

2011

multi-centre RCT

PBO+GLIM

145

60.3±10.16

74(51.0)

8.15±0.74 

NR

7.4±5.7 

24

DAPA 2.5 mg/d+GLIM

154

 

59.9±10.14 

77(50.0) 

8.11±0.75 

NR

7.7±6.0

DAPA 5 mg/d+GLIM

142

 

60.2±9.73

71(50.0)

8.12±0.78

NR

7.4±5.7 

DAPA 10 mg/d+GLIM

151

 

58.9±8.32

66 (43.7)

8.07±0.79

NR

7.2±5.5

Nauck4

2014

multi-centre RCT

DAPA 10 mg/d+MET

400

 

58±9

179(44.8) 

7.7±0.9

31.7±5.1

6±5

104

GLIP+MET

401

59±10

181(45.1)

7.7±0.9

31.2±5.1

7±6

Mudaliar41

2014

multi-centre RCT

PBO 

21

53.3±8.0

7(33.3) 

7.5±0.7

NR

6.4±5.0

12

DAPA 5 mg/d

23

56.2±8.9

8(34.8)

7.5±0.8

NR

9.9±6.5

Frias42

2020

multi-centre RCT

GLIM+MET

216

56.1±9.2

115(53.2)

8.5±0.82

32.2±5.1

7.9±6.5

52

DAPA 10 mg/d+SAXA+MET 

227

 

56.1±10.1

110(48.5) 

8.41±0.82

32.4±5.3

7.7±6.4

Handelsman43

2019

multi-centre RCT

SITA+MET

229

55.8±9.6

119 (52.0)

8.9±0.9

NR

8.2±5.2 

52

DAPA 10 mg/d+SAXA+MET 

232

 

55.9±8.9

132 (56.9)

8.8±0.8

NR

7.9±5.7

Jabbour44

2020

multi-centre RCT

EXEN+DAPA 10 mg/d

228

53.8±9.82

126(55.3)

9.3±1.1

33.2±6.8

7.6±6.0

104

EXEN+PBO

227

54.2±9.62

111(48.9)

9.3±1.1

32.0±5.9

7.4±5.5

DAPA 10 mg/d+PBO

230

54.5±9.16

102 (44.7)

9.3±1.0

33±6.1

7.1±5.5

Tina45

2020

multi-centre RCT

DAPA 10 mg/d+SAXA 

324

55.3±9.63

148 (45.7)

9.0±1.0

32.5±5.3

9.6±6.5

52

INS

319

55.7±9.52

148 (46.4)

9.1±1.1

32.0±5.4

9.3±6.2

Ferrannini46

2010

multi-centre RCT

PBO 

75

52.7±10.3

44(58.7)

7.84±0.87

32.3±5.5

0.50(0.10-3.40)

24

DAPA 2.5 mg(morning)

65

53.0±11.7

29(44.6)

7.92±0.90

32.6±5.5

0.50(0.1-2.90)

DAPA 5 mg(morning)

64

52.6±10.9

33(51.6)

7.86±0.94

31.9±4.8

0.25(0.10-1.40)

DAPA 10 mg(morning)

70

50.6±9.97

34(48.6)

8.01±0.96

33.6±5.4

0.45(0.10-3.40)

DAPA 2.5 mg(evening)

67

54.3±11.5

29(43.3)

7.99±0.99

32.2±5.3

0.20(0.10-1.20)

DAPA 5 mg(evening)

68

54.5±11.0

29(42.6)

7.82±0.91

32.8±5.3 

0.50(0.15-2.20)

DAPA 10 mg(evening)

76

50.7±9.7

39(51.3)

7.99±1.05

33.3±5.6

0.40(0.10-2.45) 

Kaku47

2013

multi-centre RCT

PBO

54

58.4±10.0

11(20.4)

8.12±0.71 

NR

4.74±3.82

12

DAPA 2.5 mg/d 

56

57.7±9.3

17(30.4)

7.92±0.74

NR

4.41±3.97

Lee48

2021

multi-centre RCT

DAPA 10 mg/d

41

59.7±8.0

24(58.5)

8.30±0.77 

27.3±3.9 

15.1±7.2

12

PBO

43

57.7±7.3 

25(58.1)

8.25±0.69 

26.6±3.0 

15.1±6.0

 

Abbreviations: DAPA,dapagliflozin;PBO,placebo;SITA,sitagliptin;EXEN,Exenatide;MET,metformin;SAXA,saxagliptin;GLIM,glimepiride;GLIP,glipizide;PIOG, pioglitazone;INS,insulin;HbA1c, glycated haemoglobin; RCT, randomized controlled trial;NR, no record.