Comparative safety of different sodium-glucose transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and network meta-analysis of randomized controlled trials

Abstract

Backgrounds:

The safety of different sodium-glucose transporter 2 (SGLT-2) inhibitors remains uncertain due to the lack of head-to-head comparisons.

Methods:

This network meta-analysis (NMA) was performed to compare the safety of nine SGLT-2 inhibitors in patients with type 2 diabetes (T2DM). PubMed, Embase, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched for studies published in English before August 30, 2022. Published and unpublished randomized controlled trials (RCTs) comparing the safety of individual SGLT-2 inhibitors in patients with T2DM were included. A Bayesian NMA with random effects model was applied. Subgroup and sensitivity analyses were performed. The quality of the evidence was evaluated using the Confidence in Network Meta-Analysis framework.

Results:

Nine SGLT-2 inhibitors were evaluated in 113 RCTs (12 registries) involving 105,293 adult patients. Reproductive tract infections (RTIs) were reported in 1,967 (4.51%) and 276 (1.01%) patients in the SGLT-2 inhibitor and placebo groups, respectively. Furthermore, pollakiuria was reported in 233 (2.66%) and 45 (0.84%) patients, respectively. Compared to placebo, a significantly higher risk of RTIs was observed with canagliflozin, ertugliflozin, empagliflozin, remogliflozin, dapagliflozin, and sotagliflozin, but not with luseogliflozin and ipragliflozin, regardless of gender. An increased risk of pollakiuria was observed with dapagliflozin [odds ratio (OR) 10.40, 95% confidence interval (CI) 1.60-157.94) and empagliflozin (OR 5.81, 95%CI 1.79-32.97). Remogliflozin (OR 6.45, 95%CI 2.18-27.79) and dapagliflozin (OR 1.33, 95%CI 1.10-1.62) were associated with an increased risk of urinary tract infections (UTIs). Instead, the included SGLT-2 inhibitors had a protective effect against acute kidney injury (AKI). No significant differences were found for hypovolemia, renal impairment or failure, fracture, diabetic ketoacidosis (DKA), amputation, and severe hypoglycemia between the SGLT-2 inhibitor and the placebo groups.

Conclusion:

In patients with T2DM, dapagliflozin was associated with an increased risk of RTIs, pollakiuria, and UTIs. Empagliflozin increased the risk of RTIs and pollakiuria. Remogliflozin increased the risk of UTIs. None of the SGLT-2 inhibitors showed a significant difference from the placebo for hypovolemia, renal impairment or failure, fracture, DKA, amputation, and severe hypoglycemia. The findings guide the selection of SGLT-2 inhibitors for patients with T2DM based on the patient’s profiles to maximize safety.

Systematic review registration:

https://www.crd.york.ac.uk/prospero, identifier CRD42022334644.

1 Introduction

Sodium-glucose transporter 2 (SGLT2) inhibitors are a new class of oral anti-diabetic drugs with evidence of improvement in metabolic syndrome and cardiovascular outcomes. SGLT2 inhibitors are recommended as first-line treatment in patients with type 2 diabetes mellitus (T2DM) and heart failure, especially heart failure with decreased ejection fraction (1). SGLT2 inhibitors may be associated with an increased risk of reproductive tract infections (RTIs), pollakiuria, hypovolemia, urinary tract infections (UTIs), and other adverse effects. However, the evidence differed between trials (2–6), all of which compared a single SGLT2 inhibitor with a placebo. Head-to-head comparisons were published only in three studies and one registry, which found that empagliflozin had a lower risk of urinary and genital infection than dapagliflozin (7, 8) A network meta-analysis (NMA) conducted in 2016 showed that dapagliflozin (10 mg) was associated with an increased risk of UTI compared to empagliflozin (25 mg) (6) Furthermore, concerns have been raised about the potential safety of individual SGLT2 inhibitors.

Although three NMAs analyzed the safety differences between SGLT2 inhibitors, the number of drugs and related adverse reactions included was limited (6, 9, 10). Whether the class safety profiles can represent individual SGLT2 inhibitors remains to be clarified. Therefore, this systematic review and NMA of randomized controlled trials (RCTs) aimed to evaluate the relative safety of nine SGLT2 inhibitors regarding RTIs, pollakiuria, hypovolemia, renal impairment/failure, acute kidney injury (AKI), UTIs, fracture, diabetic ketoacidosis (DKA), amputation, and severe hypoglycemia in patients with T2DM.

2 Materials and methods

This NMA followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension statement (11). The protocol was registered in the International Prospective Register of Systematic Review (PROSPERO, registration number CRD42022334644).

2.1 Data sources, search strategies, and study selection

We searched PubMed, Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials.gov for RCTs comparing SGLT2 inhibitors to placebo or other SGLT2 inhibitors in T2DM patients from the inception to August 30, 2022. The search consisted of three domains: intervention (SGLT2 inhibitor class or individual drugs), adverse events of particular interest, and RCTs. Details of the search strategy are provided in Appendix 2.

2.2 Selection of studies

The literature screening used PICOS (participants, intervention, comparison, outcomes and characteristics, and study design). RCTs were included if they met the following criteria: 1) T2DM patients ≥ 18 years old; 2) patients who received SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, tofogliflozin, luseogliflozin, ipragliflozin, remogliflozin, or sotagliflozin) with doses equal or greater than the approved doses for at least 12 weeks; 3) the comparator was placebos or any of the nine SGLT2 inhibitors; and 4) studies evaluated safety outcomes. Only RCTs with a sample size in the single group (sum of all dose groups) greater than 50 were included.

Primary outcomes were the risks of RTIs and pollakiuria. Secondary outcomes were the risks of hypovolemia, renal impairment and failure, AKI, UTI, fracture, DKA, amputation, and severe hypoglycemia. Two authors (LY Liu and CX Zhang) independently performed the literature search and study selection using Endnote 18.0. Disagreements were resolved by a third author (CX Li).

2.3 Data extraction

Two authors (LY Liu and CX Zhang) independently completed the data extraction using a standardized form and verified by the third author. The following data were extracted: study characteristics (first author, year of publication, countries/regions, follow-up time, details of the interventions, number of patients, and outcomes) and participants’ characteristics [mean or median age, percentage of women, baseline body mass index (BMI), median hemoglobin A1c level, and stage of renal impairment].

2.4 Risk of bias and certainty of evidence assessment

Two authors independently assessed the risk of bias in eligible studies using the revised Cochrane Collaboration Risk of Bias 2 (RoB2) tool for RCTs (12). Any discrepancies were resolved by consensus with a third author. We assessed all endpoints from the five domains, and the overall risk of bias was rated as “low risk,” “some concerns,” and “high risk.”

We used the Confidence in Network Meta-Analysis (CINeMA) framework and the Web application to evaluate confidence in the NMA results. CINeMA offers a more comprehensive approach to assessing the quality of evidence in NMA (13). CINeMA considers six domains that affect the confidence level in the NMA results: within-study bias, reporting bias, indirectness, imprecision, heterogeneity, and incoherence. The level of concern for each relative treatment effect of NMA gives rise to “no concerns,” “some concerns,” or “major concerns” in each of the six domains. Then, the judgments in all domains are summarized into a single confidence rating (“high,” “moderate,” “low,” or “very low”). The percentage contribution matrix and the weighted average risk of bias were applied to assess the within-study bias and the indirectness of each comparison.

2.5 Data synthesis

We performed Bayesian random-effects NMA of all outcomes. Dichotomous outcomes were calculated as odds ratios (OR) and 95% confidence intervals (CI). Model convergence was monitored and visualized using trace, density, and Brooks-Gelman-Rubin diagnosis plots. Good model convergence was when the potential scale reduction factor (PSRF), the median value of the shrink factor, and the 97.5% value simultaneously approached 1. The network graphs scaled by the number of patient studies by each treatment node and the risk of bias were presented graphically.

The I² estimates and their 95% CIs were used to assess heterogeneity: low (0-29%), moderate (30-59%), substantial (60-89%), and high (>89%). Subgroup analyses were used to address heterogeneity. For inconsistency, we looked at the results of node splitting. The consistency was assessed by considering direct and indirect evidence separately with node splitting. Treatment rankings were evaluated using the surface under the cumulative ranking curve (SUCRA). SUCRA values range from 0 to 100%. The higher the SUCRA value, and the closer to 100%, the higher the probability that a therapy is in the top rank or one of the top ranks.

All analyses were performed using four Markov chains (50,000 iterations after a burn-in of 10,000 and a thinning of 10). For further verification, the results were reproduced by implementing the R software (version 4.0.3) with the gemtc package (version 0.8-8) and the JAGS software (version 4.3.0). The RTIs were calculated separately for males and females. Studies focusing on T2DM with chronic kidney disease (CKD) and studies that reported extended follow-ups (≥48 weeks) were not included in the overall analysis. They were only included in the subgroup analysis. Trials with zero events in both groups were omitted from the NMA.

2.6 Sensitivity and subgroup analysis

The dose-specific network model was conducted. Subgroup analyses were performed according to renal function (estimated glomerular filtration rate (eGFR) < 90 mL/min/m²), study countries/regions (Asia, Japan, or China), types of SGLT2 inhibitor treatment (an add-on to metformin-based therapy or monotherapy in drug-naïve patients), and duration of follow-up.

3 Results

The initial screening identified 113 RCTs (n=105,293) for inclusion in the systematic review (2–5, 7, 8, 14–119) (Appendix 1). Twelve trials were published in registries (107, 108, 110–119). After reviewing data collection, 21 RCTs were excluded from NMA: 13 focused on T2DM and CKD (96–106, 108, 120), and 11 reported extended follow-ups (21, 28, 69, 89–95, 121). Among the 11 studies, 8 had only extended follow-up data, and 3 had short (24-28 weeks) and extended follow-up results (only extended follow-up outcomes were excluded).

3.1 Characteristics of included studies

Appendix 4 shows the characteristics of the included studies, including 78 (69.0%) multinational studies, 25 (22.1%) Japanese studies, and 6 (5.3%) conducted in other Asia regions. The median number of patients was 133 [33-8,582, interquartile range (IQR) 140], and the median age was 57.4 years (48.7-70.5). Twenty-three studies (20.35%) enrolled 50% or more women. The patients were primarily overweight, with a median baseline BMI of 30.7 (23.36-36.04). Most patients had a baseline median hemoglobin A1c of 8.1% (6.87-10.10). Among these studies, 90 (79.7%) studies were patients with T2DM alone, 13 (11.5%) were patients with T2DM with CKD, and 10 (8.9%) were patients with T2DM with cardiovascular disease and/or hypertension. Seventy-five studies (66.4%) (n=53,658) reported the average time since diabetes diagnosis, with a median of 7.2 years (0.25-20.70, IQR 5.67).

SGLT-2 inhibitors were used as monotherapy in drug-naive patients (20 trials; 5,714 patients) or as an addition to metformin-based therapy (25 trials; 9,957 patients). A total of 109 (96.5%) of the studies were placebo-controlled, and 4 (3.5%) had an active SGLT-2 inhibitor as a comparator. The types of intervention were dapagliflozin (5-50 mg/d, 34 studies), empagliflozin (10-50 mg/d, 26 studies), ipragliflozin (50-300 mg/d, 18 studies), canagliflozin (100-600 mg/d, 17 studies), sotagliflozin (200-400 mg/d, 11 studies), ertugliflozin (5-25 mg/d, 8 studies), luseogliflozin (2.5-10 mg/d, 8 studies), tofogliflozin (20-40 mg/d, 3 studies), and remogliflozin (200-2000 mg/d, 3 studies). The median duration of the intervention was 24 weeks (12-338). Eleven studies had a short follow-up of 24 to 28 weeks and an extended follow-up of 48 to 102 weeks.

3.2 Assessment of risk of bias

The quality of the studies varied (Appendix 5). No studies had high risks of bias for the randomization process, deviations from the intended intervention, the measurement of the outcome, and the selection of the reported result. Two studies (1.9%) had a high risk of missing outcome data. Overall, 77 studies (73.3%) had a low risk of bias (overall bias score of 1), 26 (24.8%) had some concerns (overall bias score of 2), and 2 (1.9%) had a high risk of bias (overall bias score of 1) (Appendix 5.1). The risk of bias for each outcome is shown in the RoB chart (Appendix 5.2).

3.3 Primary outcome: reproductive tract infections

Seventy-nine RCTs (n=70,850) (2–5, 7, 8, 14–24, 26–32, 34–76, 78–80, 83, 85–88, 112, 115, 117, 118) (four published in registries) reported 2, 243 (3.2%) cases of RTIs: 1,967 (4.5%) in the SGLT-2 inhibitor group and 276 (1.0%) in the placebo group. RTIs were reported in patients treated with canagliflozin (552, 6.7%), ertugliflozin (385, 5.5%), empagliflozin (536, 5.1%), sotagliflozin (21, 3.3%), remogliflozin (23, 2.9%), dapagliflozin (412, 2.9%), ipragliflozin (26, 2.2%), tofogliflozin (5, 1.3%), and luseogliflozin (7, 1.3%). Details are shown in Table 1.

The pooled OR of tofogliflozin had a wide 95% CI, which reduced the confidence of the results. Therefore, related studies were excluded from the NMA (2, 14, 15). Head-to-head comparative studies (sotagliflozin and empagliflozin, empagliflozin and dapagliflozin, remogliflozin and dapagliflozin) are shown in the network plot (Figure 1), which contributed 6.3%, 2.5%, and 8.1% to the entire network, respectively (Appendix 12.1). The trace and density plots showed good model convergence (Appendix 6.1). The PSRF was 1.01 on the Brooks-Gelman-Rubin diagnosis plot (Appendix 6.1).

Figure 1

Canagliflozin, ertugliflozin, empagliflozin, remogliflozin, dapagliflozin, and sotaglifozin were associated with a significant increase in RTIs compared to placebo. In contrast, luseogliflozin and ipragliflozin were unrelated to the risk of RTIs (Figure 2A; Table 2). The certainty of the evidence was low to high (Appendix 17.1). Compared to sotagliflozin or luseogliflozin, the risk of RTIs was not significantly different between individual SGLT-2 inhibitors (Figure 2B; Table 2).

Figure 2

There was moderate heterogeneity between the studies (I² pairwise and consistency was 35.60% and 36.41%, and the P-value of inconsistency was > 0.1) (Appendix 11.1). The SUCRA value of dapagliflozin, sotagliflozin, remogliflozin, empagliflozin, ertugliflozin, canagliflozin, luseogliflozin, ipragliflozin, and placebo was 0.81, 0.76, 0.70, 0.59, 0.54, 0.41, 0.32, 0.31, and 0.03, respectively. Dapagliflozin was ranked highest for the increased risk of RTIs (Figure 3A). Comparison-adjusted funnel plots did not suggest the presence of small study bias (Appendix 14.1).

Figure 3

RTIs were reported in 519 (4.1%) of the men in the SGLT-2 inhibitor group compared to 61 (1.0%) in the placebo group. In contrast, 635 (8.4%) of the women reported RTIs in the SGLT-2 inhibitor group compared to 85 (2.22%) in the placebo group. Women had the same risk of RTIs between ipragliflozin, ertugliflozin, canagliflozin, empagliflozin, and dapagliflozin. However, higher ORs in RTIs were observed in men compared to women (Appendices 7.1-7.2 and 8.1-8.2).

3.4 Primary outcome: pollakiuria

Twenty-five RCTs (n=14,117) (4, 7, 8, 14, 17, 18, 20, 24, 26, 27, 32, 56, 59, 65, 66, 69, 71, 75, 77, 79–81, 110, 117, 119) (three published in the registries) reported 278 (1.9%) cases of pollakiuria: 233 (2.7%) in the SGLT-2 inhibitor group and 45 (0.8%) in the placebo group. Among the 233 cases in the SGLT-2 inhibitor group, the number of pollakiuria cases was luseogliflozin (17, 7.1%), dapagliflozin (22, 6.7%), ipragliflozin (33, 5.9%), sotagliflozin (10, 4.0%), empagliflozin (95, 3.9%), ertugliflozin (12, 1.7%), tofogliflozin (2, 1.5%), and canagliflozin (42, 1.0%) (Table 1).

The 95% CI of the tofogliflozin combined OR was wide, so the related study (14) was excluded from the NMA. Finally, 24 RCTs were included. Head-to-head comparative studies between empagliflozin and dapagliflozin were found in the network plot (Figure 1). The direct comparison contributed 88.5% and 12.4% to the mixed estimates and the entire network, respectively (Appendix 12.2).

The trace and density plots showed good model convergence, and the PSRF was 1.00 in the Brooks-Gelman-Rubin diagnosis plot (Appendix 6.2). Dapagliflozin (OR 10.40, 95%CI 1.60-157.94) and empagliflozin (OR 5.81, 95%CI 1.79-32.97) increased the risk of pollakiuria compared to placebo (Figure 2C; Table 2). The certainty of the evidence was low to high (Appendix 17.2). Canagliflozin, ertugliflozin, sotagliflozin, luseogliflozin, and ipragliflozin were not associated with the risk of pollakiuria (Figure 2C; Table 2). Compared to dapagliflozin, other SGLT-2 inhibitors had the same risk of pollakiuria (Figure 2D; Table 2).

There was moderate heterogeneity between the studies (I² pairwise and consistency was 41.40% and 45.56%, and the P-value of inconsistency was > 0.1) (Appendix 11.2). The SUCRA value of dapagliflozin, ertugliflozin, sotagliflozin, empagliflozin, luseogliflozin, canagliflozin, ipragliflozin, and placebo was 0.79, 0.76, 0.67, 0.65, 0.43, 0.33, 0.28, and 0.09, respectively. Dapagliflozin ranked highest for an increased risk of pollakiuria (Figure 3B).

3.5 Secondary outcomes

The numbers of cases reported for secondary outcomes were: hypovolemia [824 (2.4%) vs. 477 (2.0%)], renal impairment or failure [177 (1.7%) vs. 97 (1.2%)], AKI [506 (2.0%) vs. 420 (2.2%)], UTIs [3,133 (6.8%) vs. 1,457 (5.1%)], fracture [957 (3.4%) vs. 670 (3.3%)], DKA [73 (0.3%) vs. 18 (0.1%)], amputation [238 (1.6%) vs. 160 (1.4%)], and severe hypoglycemia [434 (1.9%) vs. 292 (1.9%)] in the SGLT-2 inhibitor and placebo groups, respectively. Appendix 7.3–7.10 shows the network plot. The trace, density, and Brooks-Gelman-Rubin diagnosis plots showed good model convergence (Appendix 6.3–6.10). The details are shown in Table 1. The contribution graphs are shown in Appendix 12.3–12.10.

The SGLT-2 inhibitors included were not associated with the risk of hypovolemia, renal impairment or failure, fracture, DKA, amputation, or severe hypoglycemia compared to the placebo (Appendices 8.3-8.10 and 9.3–9.10). The certainty of the evidence was very low to low (Appendix 17.3–17.10). Furthermore, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin demonstrated a protective effect on AKI, but the difference was not statistically significant compared to placebo(Appendices 8.5 and 9.5).

Remogliflozin (OR 6.45, 95%CI 2.18-27.79) and dapagliflozin (OR 1.33, 95%CI 1.10-1.62) were associated with an increased risk of UTIs compared to placebo. In contrast, empagliflozin, sotagliflozin, canagliflozin, ertugliflozin, ipragliflozin, and tofogliflozin did not show significant differences with placebo. The certainty of the evidence was low to high (Appendix 17.6). Remogliflozin (OR 4.86, 95%CI 1.66-20.88) increased the risk of UTIs, while empagliflozin (OR 0.78, 95%CI 0.61-0.99) decreased the risk of UTIs when compared to dapagliflozin (Appendices 8.6 and 9.6).

Tofogliflozin and luseogliflozin ranked the worst for hypovolemia, with a value of SUCRA of 0.68 and 0.81, respectively. Dapagliflozin ranked worst for renal impairment or failure with a SUCRA value of 0.84. Remogliflozin and dapagliflozin ranked worst for UTIs, with a value of SUCRA 1.00 and 0.75, respectively (Appendix 13.1).

3.6 Subgroup analysis

3.6.1 Subgroup analysis according to doses

The risk of RTIs increased with increasing doses of dapagliflozin (5 to 50 mg/d) and ertugliflozin (5 to 20 mg/d, except 10 mg/d). The certainty of the evidence was very low to high. In split-dose studies, subgroup analysis of canagliflozin 600 mg/d (24), empagliflozin 50 mg/d (59, 61), ertugliflozin 10 mg/d (19), remogliflozin 250 mg/d (87), and remogliflozin 1000 mg/d (86, 87) was inconsistent with the overall analysis, suggesting that there was no increased risk of RTIs at these drug doses. Canagliflozin 200 mg/d in women (29, 61) and empagliflozin 50 mg/d (61) in men showed opposite results compared to the overall analysis (Appendix 15.1).

Subgroup analyses showed that, in split-dose studies, the risks of pollakiuria (except empagliflozin 50 mg/d (59) and ertugliflozin 15 mg/d (4, 20)), UTIs (except high dose dapagliflozin 20 mg/d (5, 35) and 50 mg/d (5), remogliflozin low dose 200 mg/d (86, 88) and 250 mg/d (87)), and fracture were consistent with the overall analyses. The certainty of the evidence was low to high (Appendix 15.1).

Subgroup analyses showed that the risks of hypovolemia (except canagliflozin 300 mg/d), AKI, and severe hypoglycemia were consistent with the overall analyses. The certainty of the evidence was low. Low- to moderate-quality evidence showed the same renal impairment or failure results. Very low to low-quality evidence showed similar results regarding DKA and amputation.

3.6.2 Subgroup analysis according to different regions

Twenty-five RCTs (n=7,162) reported 113 (2.2%) and 11(0.5%) cases of RTIs in Asia treated with SGLT-2 inhibitors and placebo, respectively (2, 3, 7, 8, 15–18, 22, 29, 31, 32, 41, 42, 49, 52, 53, 61, 69, 71, 76, 78–80, 88). NMA with 23 RCTs suggested empagliflozin and dapagliflozin were associated with an increased risk of RTIs, but not for luseogliflozin, ipragliflozin, canagliflozin, ertugliflozin, and remogliflozin. Similar results were obtained from NMA with 17 RCTs conducted in Japan (2, 3, 15–18, 29, 32, 41, 49, 61, 69, 71, 76, 78–80). Two RCTs from China (22, 42) suggested that dapagliflozin but not ertugliflozin was associated with an increased risk of RTIs (Appendix 15.2).

Twelve RCTs (n=2,602) reported 106 (5.9%) and 20 (2.5%) cases of pollakiuria in Asia treated with SGLT-2 inhibitors and placebo, respectively (7, 8, 17, 18, 32, 69, 71, 75, 77, 79–81). NMA with 12 RCTs from Asia and 9 RCTs from Japan (17, 18, 32, 69, 71, 75, 77, 79, 80) suggested that the SGLT-2 inhibitors (empagliflozin and dapagliflozin in Asia and empagliflozin in Japan) were not associated with an increased risk of pollakiuria. Subgroup analyses of other SGLT-2 inhibitors were consistent with the overall analysis (Appendix 15.2).

Fifteen RCTs (n=4,429) reported 52 (1.7%) and 13 (0.9%) cases of hypovolemia (2, 3, 8, 15–17, 22, 29, 31, 53, 61, 69, 71, 80, 84), five RCTs (n=1,450) reported 17 (1. 9%) and 15 (2.7%) cases of renal impairment or failure (18, 42, 49, 52, 53), and 27 RCTs (n=7,411) reported 172 (3.3%) and 63 (2.9%) cases of UTIs (2, 7, 8, 15, 17, 22, 29, 31–33, 41, 42, 49, 52, 53, 61, 69, 71, 75, 76, 78–82, 84, 88) in Asians treated with SGLT-2 inhibitors and placebo, respectively. NMAs of 26 RCTs in Asia and 16 from Japan demonstrated that dapagliflozin and remogliflozin were not associated with an increased risk of UTIs. Other outcomes in Asia and Japan were consistent with the overall analysis (Appendix 15.2).

3.6.3 Subgroup analysis in patients with CKD

Subgroup analyses were performed for the 13 studies focusing on T2DM with CKD (eGFR<90 ml/min/1.73m²) (96–106, 108, 120). Similar results were obtained regarding pollakiuria, renal impairment or failure, fracture, and severe hypoglycemia compared to the overall analyses. However, opposite results were obtained regarding RTIs for empagliflozin, dapagliflozin, and sotagliflozin; hypovolemia for ertugliflozin and luseogliflozin; AKIs for dapagliflozin and sotagliflozin; and UTIs, DKA, and amputation for dapagliflozin in the subgroup analyses compared to the overall analyses (Appendix 15.3).

3.7 Sensitivity analysis

3.7.1 Sensitivity analysis according to the interventions

Sensitivity analyses of SGLT-2 inhibitors as an add-on therapy to metformin-based treatment showed similar results for hypovolemia and renal impairment or failure compared to the overall analyses. Fewer included SGLT-2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, and remogliflozin) were associated with risk of RTIs [dapagliflozin (OR 5.06, 95%CI 1.21-54.57) and empagliflozin (OR 10.86, 95%CI 2.52-116.23)]. All included SGLT-2 inhibitors were not associated with a risk of pollakiuria (canagliflozin, empagliflozin, and ipragliflozin) and UTIs (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, sotaglifozin, tofogliflozin, and remogliflozin). Details are shown in Appendix 16.1.

Subgroup analyses of drug-naive patients showed similar outcome results for pollakiuria, hypovolemia, and renal impairment or failure as the overall analysis. The results were similar to metformin-based treatment (Appendix 16.1).

3.7.2 Sensitivity analysis according to the follow-up period

The risks of RTIs (canagliflozin, dapagliflozin, ertugliflozin, empagliflozin), pollakiuria (canagliflozin and empagliflozin), hypovolemia (canagliflozin, dapagliflozin, ertugliflozin, empagliflozin) and UTIs (canagliflozin, dapagliflozin, ertugliflozin, empagliflozin, expect dapagliflozin in short-term follow-up studies) of the included SGL-2 inhibitors were consistent with the overall analysis regardless of the follow-up time (Appendix 16.2).

4 Discussion

Only four head-to-head RCTs (7, 8, 88, 112) compared individual SGLT-2 inhibitors in T2DM. The comparative safety of specific SGLT-2 inhibitors remains unclear. NMA is an increasingly popular tool for comparative effectiveness or safety research. Three NMAs have compared the safety profiles of different SGLT-2 inhibitors regarding UTIs, focusing mainly on canagliflozin, empagliflozin, and dapagliflozin (6, 9, 10). A study compared the risk of RTIs, UTIs, and hypoglycemia among dapagliflozin, canagliflozin, and empagliflozin in patients with T2DM (6). Another study compared the risk of hypovolemia among dapagliflozin, canagliflozin, and empagliflozin in T2DM (10). The third study compared the risk of UTIs among dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, bexagliflozin, and sotagliflozin in T2DM patients with CKD (9). This is the first comprehensive analysis comparing safety evidence of nine SGLT-2 inhibitors in patients with T2DM regarding ten adverse events (especially new outcomes: pollakiuria, renal impairment or failure, and AKI).

Most of the included studies reported RTIs (79 studies), pollakiuria (25 studies), hypovolemia (42 studies), renal impairment or failure (21 studies), and UTIs (89 studies). Few included studies reported AKI (9 studies), fracture (20 studies), DKA (7 studies), amputation (4 studies), and severe hypoglycemia (15 studies). Most patients were treated with canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and ertugliflozin. Few included studies enrolled patients treated with remogliflozin, sotagliflozin, tofogliflozin, and luseogliflozin. Therefore, outcomes based on a few studies, especially those with wider confidence intervals, should be interpreted cautiously. Further verification from more high-quality and large-sample studies is necessary.

4.1 Primary outcomes: RTIs

Luseogliflozin and ipragliflozin were not associated with an increased risk of RTIs. Therefore, not all SGLT-2 inhibitors increased the risk of RTIs, which differed from a previous study (6). The participants in the luseogliflozin trial were all Japanese, and most of the participants included in the ipragliflozin trial were Japanese. SGLT-2 inhibitors seem safer in the Asian population, and the association of luseogliflozin and ipragliflozin with the risk of RTIs should be studied in more ethnic groups. The subgroup analysis indicated that individual SGLT-2 inhibitors were not associated with the risk of RTIs in Asia. A meta-analysis also showed that SGLT-2 inhibitors were associated with a similar risk of RTIs compared to placebo in Japanese patients with T2DM (122).

The subgroup analysis showed that the risk of RTIs increased with increasing doses of dapagliflozin or ertugliflozin. Due to the few included studies and the few events, several doses of SGLT-2 inhibitors showed inconsistent results with wide confidence intervals and, therefore, should be interpreted cautiously.

4.2 Primary outcomes: pollakiuria

Dapagliflozin and empagliflozin increased the risk of pollakiuria in T2DM compared to placebo (with incidence rates of 6.73% and 3.89%). Similar results were also shown in the subgroup analyses of CKD and drug-naive patients. However, individual SGLT-2 inhibitors were not associated with a risk of pollakiuria in Asia. Several real-world studies from Asia have also shown lower pollakiuria rates in patients treated with SGLT-2 inhibitors. A Korean post-marketing surveillance study of empagliflozin (10 and 25 mg) revealed that the most common adverse event was pollakiuria, with incidence rates of 0.59% (123). A Japanese post-marketing surveillance study of 100 mg of canagliflozin showed that the most common adverse event was pollakiuria, with an incidence rate of 0.79% (124). A 36-month post-marketing surveillance study found that the pollakiuria incidence rate of tofogliflozin was 1.3% in Japanese patients (125). A study found that the increase in urine output was transient, with a return to baseline on day 2 to day 5 of treatment (126). Therefore, pollakiuria may be tolerated over time.

4.3 Secondary outcomes

The nine SGLT-2 inhibitors were not associated with the risk of hypovolemia, renal impairment or failure, fracture, DKA, amputation, and severe hypoglycemia compared to the placebo. Two meta-analyses found that the SGLT-2 inhibitor class was associated with an increased risk of hypovolemia, which differs from our study (127, 128). The subgroup analysis showed that canagliflozin 300 mg was associated with a significantly increased risk of hypovolemia, consistent with a previous meta-analysis (10).

Remogliflozin and dapagliflozin were associated with an increased risk of UTIs. Dapagliflozin 10 mg/d increased the risk of UTIs compared to placebo and empagliflozin 25 mg/d (6). However, a meta-analysis of three RCTs suggested that remogliflozin was not associated with UTIs. Differences may be caused by effect sizes (relative risk versus OR) (129). The subgroup analysis indicated that individual SGLT-2 inhibitors were not associated with the risk of UTIs in Asia.

4.4 Sensitivity analyses

A 3-year Japanese post-marketing surveillance study showed that drug-naive patients had significantly lower incidences of adverse events (10.81% vs. 20.87%; P < 0.001) and serious adverse events (0.86% vs. 2.09%; P < 0.001) compared to non-naive patients, as well as significantly lower incidences of pollakiuria, volume depletion-related events, and kidney disorders (130). Sensitivity analysis showed that adverse drug reactions were similar between SGLT-2 inhibitor monotherapy and add-on therapies to metformin. Few SGLT-2i were associated with the risk of RTIs, pollakiuria and UTIs compared to overall analysis, which should be interpreted with caution, as it could be affected by the number of studies and sample sizes.

Although the included studies had follow-up times ranging from 12 to 338 weeks, the median duration was 24 weeks. The sensitivity analysis based on the follow-up time showed broadly consistent results. The incidence of related adverse events in extended follow-up studies was higher than in short-term studies because the sample size was unchanged and the number of events accumulated. A 3-year Japanese post-marketing surveillance study showed that the long-term safety profile of ipragliflozin treatment in routine clinical practice was consistent with previously reported interim data at 12 or 24 months and pre-approval clinical trials (131).

4.5 The limitations of our study

The present NMA included all available evidence on the safety outcomes of all SGLT-2 inhibitors in patients with T2DM. Considering the homogeneity of the included studies, we deliberately excluded studies that focus on specific populations (such as T2DM with heart failure or BMI≥35 kg/m² or years of age > 65 or with CKD). Meanwhile, studies with a sample size of less than 50 or with a study period of fewer than 12 weeks were excluded. Our study has several limitations. First, most of the included studies were individual SGLT-2 inhibitors versus placebo, and only four studies were conducted to compare different SGLT-2 inhibitors. Direct comparisons contributed little to these NMA results, resulting in wider CIs, greater uncertainty, and lower confidence in the evidence evaluated by CINeMA. Second, most of the included studies had a relatively small number of patients (less than 300), only ten studies had a larger sample size of 500-9,000. Third, given the limited availability of data on individual SGLT-2 inhibitors or subgroup analysis, caution is recommended when interpreting these results.

5 Conclusions

Not all SGLT-2 inhibitors increased the risk of RTIs. Luseogliflozin and ipragliflozin were not associated with an increased risk of RTIs. Dapagliflozin ranked first in increasing the risk of RTIs. Dapagliflozin and empagliflozin increased the risk of pollakiuria. Remogliflozin and dapagliflozin increased the risk of UTIs, and remogliflozin ranked first. SGLT-2 inhibitors were not associated with the risk of hypovolemia, renal impairment or failure, fracture, DKA, amputation, and severe hypoglycemia compared to placebo. Active-controlled trials comparing SGLT2 inhibitors are urgently needed to validate the estimates of the comparative safety produced in this network meta-analysis.

References

• 1

  Buse JB Wexler DJ Tsapas A Rossing P Mingrone G Mathieu C et al . 2019 update to: management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American diabetes association (ADA) and the European association for the study of diabetes (EASD). Diabetes Care (2020) 43(2):487–93. doi: 10.2337/dc20–er07

  • CrossRef
  • Google Scholar

• 2

  Kaku K Watada H Iwamoto Y Utsunomiya K Terauchi Y Tobe K et al . Efficacy and safety of monotherapy with the novel sodium/glucose cotransporter–2 inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus: a combined Phase 2 and 3 randomized, placebo–controlled, double–blind, parallel–group comparative study. Cardiovasc Diabetol (2014) 13(1):65. doi: 10.1186/1475–2840–13–65

  • CrossRef
  • Google Scholar

• 3

  Seino Y Sasaki T Fukatsu A Sakai S Samukawa Y . Efficacy and safety of luseogliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: a 12–week, randomized, placebo–controlled, phase II study. Curr Med Res Opin (2014) 30(7):1219–30. doi: 10.1185/03007995.2014.901943

  • CrossRef
  • Google Scholar

• 4

  Rosenstock J Frias J Pall D Charbonnel B Pascu R Saur D et al . Effect of ertugliflozin on glucose control, body weight, blood pressure and bone density in type 2 diabetes mellitus inadequately controlled on metformin monotherapy (VERTIS MET). Diabetes Obes Metab (2018) 20(3):520–9. doi: 10.1111/dom.13103

  • CrossRef
  • Google Scholar

• 5

  List JF Woo V Morales E Tang W Fiedorek FT . Sodium–glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care (2009) 32(4):650–7. doi: 10.2337/dc08–1863

  • CrossRef
  • Google Scholar

• 6

  Zaccardi F Webb DR Htike ZZ Youssef D Khunti K Davies MJ . Efficacy and safety of sodium–glucose co–transporter–2 inhibitors in type 2 diabetes mellitus: systematic review and network meta–analysis. Diabetes Obes Metab (2016) 18(8):783–94. doi: 10.1111/dom.12670

  • CrossRef
  • Google Scholar

• 7

  Hussain M Atif M Babar M Akhtar L . Comparison of efficacy and safety profile of empagliflozin versus dapagliflozin as add on therapy in type 2 diabetic patients. J Ayub Med College Abbottabad (2021) 33(4):593–7.

  • Google Scholar

• 8

  Hussain M Elahi A Iqbal J Bilal Ghafoor M Rehman H Akhtar S . Comparison of efficacy and safety profile of sodium–glucose cotransporter–2 inhibitors as add–on therapy in patients with type 2 diabetes. Cureus (2021) 13(4):e14268. doi: 10.7759/cureus.14268

  • CrossRef
  • Google Scholar

• 9

  Lin J Wang S Wen T Zhang X . Renal protective effect and safety of sodium–glucose cotransporter–2 inhibitors in patients with chronic kidney disease and type 2 diabetes mellitus: a network meta–analysis and systematic review. Int Urol Nephrol (2022) 54(9):2305–16. doi: 10.1007/s11255–022–03117–4

  • CrossRef
  • Google Scholar

• 10

  Jiang Y Yang P Fu L Sun L Shen W Wu Q . Comparative cardiovascular outcomes of SGLT2 inhibitors in type 2 diabetes mellitus: A network meta–analysis of randomized controlled trials. Front Endocrinol (Lausanne) (2022) 13:802992. doi: 10.3389/fendo.2022.802992

  • CrossRef
  • Google Scholar

• 11

  Hutton B Salanti G Caldwell DM Chaimani A Schmid CH Cameron C et al . The PRISMA extension statement for reporting of systematic reviews incorporating network meta–analyses of health care interventions: checklist and explanations. Ann Intern Med (2015) 162(11):777–84. doi: 10.7326/M14–2385

  • CrossRef
  • Google Scholar

• 12

  Sterne JAC SJ Page MJ Elbers RG Blencowe NS Boutron I Boutron I et al . RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ (2019) 28:366. doi: 10.1136/bmj.l4898

  • CrossRef
  • Google Scholar

• 13

  Nikolakopoulou A Higgins JPT Papakonstantinou T Chaimani A Del Giovane C Egger M et al . CINeMA: An approach for assessing confidence in the results of a network meta–analysis. PloS Med (2020) 17(4):e1003082. doi: 10.1371/journal.pmed.1003082

  • CrossRef
  • Google Scholar

• 14

  Ikeda S Takano Y Cynshi O Tanaka R Christ AD Boerlin V et al . A novel and selective sodium–glucose cotransporter–2 inhibitor, tofogliflozin, improves glycaemic control and lowers body weight in patients with type 2 diabetes mellitus. Diabetes Obes Metab (2015) 17(10):984–93. doi: 10.1111/dom.12538

  • CrossRef
  • Google Scholar

• 15

  Terauchi Y Tamura M Senda M Gunji R Kaku K . Efficacy and safety of tofogliflozin in Japanese patients with type 2 diabetes mellitus with inadequate glycaemic control on insulin therapy (J–STEP/INS): results of a 16–week randomized, double–blind, placebo–controlled multicentre trial. Diabetes Obes Metab (2017) 19(10):1397–407. doi: 10.1111/dom.12957

  • CrossRef
  • Google Scholar

• 16

  Seino Y Sasaki T Fukatsu A Ubukata M Sakai S Samukawa Y . Dose–finding study of luseogliflozin in Japanese patients with type 2 diabetes mellitus: a 12–week, randomized, double–blind, placebo–controlled, phase II study. Curr Med Res Opin (2014) 30(7):1231–44. doi: 10.1185/03007995.2014.909390

  • CrossRef
  • Google Scholar

• 17

  Seino Y Sasaki T Fukatsu A Imazeki H Ochiai H Sakai S . Efficacy and safety of luseogliflozin added to insulin therapy in Japanese patients with type 2 diabetes: a multicenter, 52–week, clinical study with a 16–week, double–blind period and a 36–week, open–label period. Curr Med Res Opin (2018) 34(6):981–94. doi: 10.1080/03007995.2018.1441816

  • CrossRef
  • Google Scholar

• 18

  Seino Y Sasaki T Fukatsu A Ubukata M Sakai S Samukawa Y . Efficacy and safety of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, double–blind, placebo–controlled, phase 3 study. Curr Med Res Opin (2014) 30(7):1245–55. doi: 10.1185/03007995.2014.912983

  • CrossRef
  • Google Scholar

• 19

  Amin NB Wang X Jain SM Lee DS Nucci G Rusnak JM . Dose–ranging efficacy and safety study of ertugliflozin, a sodium–glucose co–transporter 2 inhibitor, in patients with type 2 diabetes on a background of metformin. Diabetes Obes Metab (2015) 17(6):591–8. doi: 10.1111/dom.12460

  • CrossRef
  • Google Scholar

• 20

  Terra SG Focht K Davies M Frias J Derosa G Darekar A et al . efficacy and safety study of ertugliflozin monotherapy in people with type 2 diabetes mellitus inadequately controlled with diet and exercise alone. Diabetes Obes Metab (2017) 19(5):721–8. doi: 10.1111/dom.12888

  • CrossRef
  • Google Scholar

• 21

  Dagogo–Jack S Liu J Eldor R Amorin G Johnson J Hille D et al . Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: the VERTIS SITA2 placebo–controlled randomized study. Diabetes Obes Metab (2018) 20(3):530–40. doi: 10.1111/dom.13116

  • CrossRef
  • Google Scholar

• 22

  Ji L Liu Y Miao H Xie Y Yang M Wang W et al . Safety and efficacy of ertugliflozin in Asian patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy: VERTIS Asia. Diabetes Obes Metab (2019) 21(6):1474–82. doi: 10.1111/dom.13681

  • CrossRef
  • Google Scholar

• 23

  Cannon CP Pratley R Dagogo–Jack S Mancuso J Huyck S Masiukiewicz U et al . Cardiovascular outcomes with ertugliflozin in type 2 diabetes. New Engl J Med (2020) 383(15):1425–35. doi: 10.1056/NEJMoa2004967

  • CrossRef
  • Google Scholar

• 24

  Rosenstock J Aggarwal N Polidori D Zhao Y Arbit D Usiskin K et al . Dose–ranging effects of canagliflozin, a sodium–glucose cotransporter 2 inhibitor, as add–on to metformin in subjects with type 2 diabetes. Diabetes Care (2012) 35(6):1232–8. doi: 10.2337/dc11–1926

  • CrossRef
  • Google Scholar

• 25

  Inagaki N Kondo K Yoshinari T Maruyama N Susuta Y Kuki H . Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double–blind, placebo–controlled, 12–week study. Diabetes Obes Metab (2013) 15(12):1136–45. doi: 10.1111/dom.12149

  • CrossRef
  • Google Scholar

• 26

  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) 41(2):72–84. doi: 10.3810/hp.2013.04.1020

  • CrossRef
  • Google Scholar

• 27

  Stenlöf K Cefalu WT Kim KA Alba M Usiskin K Tong C et al . Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab (2013) 15(4):372–82. doi: 10.1111/dom.12054

  • CrossRef
  • Google Scholar

• 28

  Wilding JP Charpentier G Hollander P González–Gálvez G Mathieu C Vercruysse F et al . Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract (2013) 67(12):1267–82. doi: 10.1111/ijcp.12322

  • CrossRef
  • Google Scholar

• 29

  Inagaki N Kondo K Yoshinari T Takahashi N Susuta Y Kuki H . Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: A 24–week, randomized, double–blind, placebo–controlled, Phase III study. Expert Opin Pharmacother (2014) 15(11):1501–15. doi: 10.1517/14656566.2014.935764

  • CrossRef
  • Google Scholar

• 30

  Qiu R Capuano G Meininger G . Efficacy and safety of twice–daily treatment with canagliflozin, a sodium glucose co–transporter 2 inhibitor, added on to metformin monotherapy in patients with type 2 diabetes mellitus. J Clin Trans Endocrinol (2014) 1(2):54–60. doi: 10.1016/j.jcte.2014.04.001

  • CrossRef
  • Google Scholar

• 31

  Ji L Han P Liu Y Yang G Dieu Van NK Vijapurkar U et al . Canagliflozin in Asian patients with type 2 diabetes on metformin alone or metformin in combination with sulphonylurea. Diabetes Obes Metab (2015) 17(1):23–31. doi: 10.1111/dom.12385

  • CrossRef
  • Google Scholar

• 32

  Inagaki N Harashima SI Maruyama N Kawaguchi Y Goda M Iijima H . Efficacy and safety of canagliflozin in combination with insulin: a double–blind, randomized, placebo–controlled study in Japanese patients with type 2 diabetes mellitus. Cardiovasc Diabetol (2016) 5:89. doi: 10.1186/s12933–016–0407–4

  • CrossRef
  • Google Scholar

• 33

  Kadowaki T Inagaki N Kondo K Nishimura K Kaneko G Maruyama N et al . Efficacy and safety of canagliflozin as add–on therapy to teneligliptin in Japanese patients with type 2 diabetes mellitus: results of a 24–week, randomized, double–blind, placebo–controlled trial. Diabetes Obes Metab (2017) 19(6):874–82. doi: 10.1111/dom.12898

  • CrossRef
  • Google Scholar

• 34

  Bailey CJ Gross JL Pieters A Bastien A List JF . Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double–blind, placebo–controlled trial. Lancet (2010) 375(9733):2223–33. doi: 10.1016/S0140–673610()60407–2

  • CrossRef
  • Google Scholar

• 35

  Ferrannini E Ramos SJ Salsali A Tang W List JF . Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: A randomized, double–blind, placebo–controlled, phase 3 trial. Diabetes Care (2010) 33(10):2217–24. doi: 10.2337/dc10–0612

  • CrossRef
  • Google Scholar

• 36

  Strojek K Yoon KH Hruba V Elze M Langkilde AM Parikh S . Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: A randomized, 24–week, double–blind, placebo–controlled trial. Diabetes Obes Metab (2011) 13(10):928–38. doi: 10.1111/j.1463–1326.2011.01434.x

  • CrossRef
  • Google Scholar

• 37

  Bailey CJ Iqbal N T'Joen C List JF . Dapagliflozin monotherapy in drug–naïve patients with diabetes: a randomized–controlled trial of low–dose range. Diabetes Obes Metab (2012) 14(10):951–9. doi: 10.1111/j.1463–1326.2012.01659.x

  • CrossRef
  • Google Scholar

• 38

  Bolinder J Ljunggren Ö Kullberg J Johansson L Wilding J Langkilde AM et al . Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab (2012) 97(3):1020–31. doi: 10.1210/jc.2011–2260

  • CrossRef
  • Google Scholar

• 39

  Rosenstock J Vico M Wei L Salsali A List JF . Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care (2012) 35(7):1473–8. doi: 10.2337/dc11–1693

  • CrossRef
  • Google Scholar

• 40

  Wilding JP Woo V Soler NG Pahor A Sugg J Rohwedder K et al . Dapagliflozin 006 Study Group. Long–term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. . Ann Intern Med (2012) 156(6):405–15. doi: 10.7326/0003–4819–156–6–201203200–00003

  • CrossRef
  • Google Scholar

• 41

  Kaku K Inoue S Matsuoka O Kiyosue A Azuma H Hayashi N et al . Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: A phase II multicentre, randomized, double–blind, placebo–controlled trial. Diabetes Obes Metab (2013) 15(5):432–40. doi: 10.1111/dom.12047

  • CrossRef
  • Google Scholar

• 42

  Ji L Ma J Li H Mansfield TA T'Joen CL Iqbal N et al . Dapagliflozin as monotherapy in drug–naive Asian patients with type 2 diabetes mellitus: a randomized, blinded, prospective phase III study. Clin Ther (2014) 36(1):84–100.e109. doi: 10.1016/j.clinthera.2013.11.002

  • CrossRef
  • Google Scholar

• 43

  Leiter LA Cefalu WT De Bruin TWA Gause–Nilsson I Sugg J Parikh SJ et al . Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: A 24–week, multicenter, randomized, double–blind, placebo–controlled study with a 28–week extension. J Am Geriatrics Soc (2014) 62(7):1252–62. doi: 10.1111/jgs.12881

  • CrossRef
  • Google Scholar

• 44

  Bailey CJ Morales Villegas EC Woo V Tang W Ptaszynska A List JF . Efficacy and safety of dapagliflozin monotherapy in people with Type 2 diabetes: a randomized double–blind placebo–controlled 102–week trial. Diabetes Med (2015) 32(4):531–41. doi: 10.1111/dme.12624

  • CrossRef
  • Google Scholar

• 45

  Cefalu WT Leiter LA De Bruin TWA Gause–Nilsson I Sugg J Parikh SJ et al . Dapagliflozin's effects on glycemia and cardiovascular risk factors in high–risk patients with type 2 diabetes: A 24–week, multicenter, randomized, double–blind, placebo–controlled study with a 28–week extension. Diabetes Care (2015) 38(7):1218–27. doi: 10.2337/dc14–0315

  • CrossRef
  • Google Scholar

• 46

  Mathieu C Ranetti AE Li D Ekholm E Cook W Hirshberg B et al . Randomized, double–blind, phase 3 trial of triple therapy with dapagliflozin add–on to saxagliptin plus metformin in type 2 diabetes. Diabetes Care (2015) 38(11):2009–17. doi: 10.2337/dc15–0779

  • CrossRef
  • Google Scholar

• 47

  Matthaei S Bowering K Rohwedder K Grohl A Parikh S . Study 05 Group. Dapagliflozin improves glycemic control and reduces body weight as add–on therapy to metformin plus sulfonylurea: a 24–week randomized, double–blind clinical trial. Diabetes Care (2015) 38(3):365–72. doi: 10.2337/dc14–0666

  • CrossRef
  • Google Scholar

• 48

  Schumm–Draeger PM Burgess L Korányi L Hruba V Hamer–Maansson JE de Bruin TW . Twice–daily dapagliflozin co–administered with metformin in type 2 diabetes: a 16–week randomized, placebo–controlled clinical trial. Diabetes Obes Metab (2015) 17(1):42–51. doi: 10.1111/dom.12387

  • CrossRef
  • Google Scholar

• 49

  Araki E Onishi Y Asano M Kim H Ekholm E Johnsson E et al . Efficacy and safety of dapagliflozin in addition to insulin therapy in Japanese patients with type 2 diabetes: Results of the interim analysis of 16–week double–blind treatment period. J Diabetes Invest (2016) 7(4):555–64. doi: 10.1111/jdi.12453

  • CrossRef
  • Google Scholar

• 50

  Weber MA Mansfield TA Alessi F Iqbal N Parikh S Ptaszynska A . Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin–angiotensin system blockade. Blood Press (2016) 25(2):93–103. doi: 10.3109/08037051.2015.1116258

  • CrossRef
  • Google Scholar

• 51

  Weber MA Mansfield TA Cain VA Iqbal N Parikh S Ptaszynska A . Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double–blind, placebo–controlled, phase 3 study. Lancet Diabetes Endocrinol (2016) 4(3):211–20. doi: 10.1016/S2213–858715()00417–9

  • CrossRef
  • Google Scholar

• 52

  Yang W Han P Min KW Wang B Mansfield T T'Joen C et al . Efficacy and safety of dapagliflozin in Asian patients with type 2 diabetes after metformin failure: A randomized controlled trial. J Diabetes (2016) 8(6):796–808. doi: 10.1111/1753–0407.12357

  • CrossRef
  • Google Scholar

• 53

  Yang W Ma J Li Y Li Y Zhou Z Kim JH et al . Dapagliflozin as add–on therapy in Asian patients with type 2 diabetes inadequately controlled on insulin with or without oral antihyperglycemic drugs: A randomized controlled trial. J Diabetes (2018) 10(7):589–99. doi: 10.1111/1753–0407.12634

  • CrossRef
  • Google Scholar

• 54

  Wiviott SD Mosenzon O Moist L . Dapagliflozin reduced cardiorenal outcomes but not MACE in T2 diabetes with or at risk for atherosclerotic CVD. Ann Internal Med (2019) 171(8):JC43. doi: 10.7326/ACPJ201910150–043

  • CrossRef
  • Google Scholar

• 55

  Frías JP Guja C Hardy E Ahmed A Dong F Öhman P et al . Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION–8): a 28 week, multicentre, double–blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol (2016) 41(2):1004–16. doi: 10.1016/S2213–858716()30267–4

  • CrossRef
  • Google Scholar

• 56

  Ferrannini E Seman L Seewaldt–Becker E Hantel S Pinnetti S Woerle HJ . A Phase IIb, randomized, placebo–controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes Metab (2013) 15(8):721–8. doi: 10.1111/dom.12081

  • CrossRef
  • Google Scholar

• 57

  Häring HU Merker L Seewaldt–Becker E Weimer M Meinicke T Woerle HJ et al . EMPA–REG METSU Trial Investigators. Empagliflozin as add–on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24–week, randomized, double–blind, placebo–controlled trial. Diabetes Care (2013) 36(11):3396–404. doi: 10.2337/dc12–2673

  • CrossRef
  • Google Scholar

• 58

  Roden M Weng J Eilbracht J Delafont B Kim G Woerle HJ et al . EMPA–REG MONO trial investigators. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double–blind, placebo–controlled, phase 3 trial. . Lancet Diabetes Endocrinol (2013) 1(3):208–19. doi: 10.1016/S2213–858713()70084–6

  • CrossRef
  • Google Scholar

• 59

  Rosenstock J Seman LJ Jelaska A Hantel S Pinnetti S Hach T et al . Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add–on to metformin in type 2 diabetes with mild hyperglycaemia. Diabetes Obes Metab (2013) 15(12):1154–60. doi: 10.1111/dom.12185

  • CrossRef
  • Google Scholar

• 60

  Häring HU Merker L Seewaldt–Becker E Weimer M Meinicke T Broedl UC et al . EMPA–REG MET Trial Investigators. Empagliflozin as add–on to metformin in patients with type 2 diabetes: a 24–week, randomized, double–blind, placebo–controlled trial. Diabetes Care (2014) 37(6):1650–9. doi: 10.2337/dc13–2105

  • CrossRef
  • Google Scholar

• 61

  Kadowaki T Haneda M Inagaki N Terauchi Y Taniguchi A Koiwai K et al . Empagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: A randomized, 12–week, double–blind, placebo–controlled, phase II trial. Adv Ther (2014) 31(6):621–38. doi: 10.1007/s12325–014–0126–8

  • CrossRef
  • Google Scholar

• 62

  Kovacs CS Seshiah V Swallow R Jones R Rattunde H Woerle HJ et al . EMPA–REG PIO™ trial investigators. Empagliflozin improves glycaemic and weight control as add–on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24–week, randomized, placebo–controlled trial. Diabetes Obes Metab (2014) 16(2):147–58. doi: 10.1111/dom.12188

  • CrossRef
  • Google Scholar

• 63

  Merker L Häring HU Christiansen AV Roux F Salsali A Kim G et al . Empagliflozin as add–on to metformin in people with Type 2 diabetes. Diabetes Med (2015) 32(12):1555–67. doi: 10.1111/dme.12814

  • CrossRef
  • Google Scholar

• 64

  Rosenstock J Jelaska A Zeller C Kim G Broedl UC Woerle HJ et al . Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: A 78–week randomized, double–blind, placebo–controlled trial. Diabetes Obes Metab (2015) 17(10):936–48. doi: 10.1111/dom.12503

  • CrossRef
  • Google Scholar

• 65

  Ross S Thamer C Cescutti J Meinicke T Woerle HJ Broedl UC . Efficacy and safety of empagliflozin twice daily versus once daily in patients with type 2 diabetes inadequately controlled on metformin: a 16–week, randomized, placebo–controlled trial. Diabetes Obes Metab (2015) 17(7):699–702. doi: 10.1111/dom.12469

  • CrossRef
  • Google Scholar

• 66

  Tikkanen I Narko K Zeller C Green A Salsali A Broedl UC et al . EMPA–REG BP Investigators. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care (2015) 38(3):420–8. doi: 10.2337/dc14–1096

  • CrossRef
  • Google Scholar

• 67

  Zinman B Wanner C Lachin JM Fitchett D Bluhmki E Hantel S et al . Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New Engl J Med (2015) 373(22):2117–28. doi: 10.1056/NEJMoa1504720

  • CrossRef
  • Google Scholar

• 68

  Søfteland E Meier JJ Vangen B Toorawa R Maldonado–Lutomirsky M Broedl UC . Empagliflozin as add–on therapy in patients with type 2 diabetes inadequately controlled with linagliptin and metformin: A 24–week randomized, double–blind, parallel–group trial. Diabetes Care (2017) 40(2):201–9. doi: 10.2337/dc16–1347

  • CrossRef
  • Google Scholar

• 69

  Kawamori R Haneda M Suzaki K Cheng G Shiki K Miyamoto Y et al . Empagliflozin as add–on to linagliptin in a fixed–dose combination in Japanese patients with type 2 diabetes: glycaemic efficacy and safety profile in a 52–week, randomized, placebo–controlled trial. Diabetes Obes Metab (2018) 20(9):2200–9. doi: 10.1111/dom.13352

  • CrossRef
  • Google Scholar

• 70

  Ferdinand KC Izzo JL Lee J Meng L George J Salsali A et al . Antihyperglycemic and blood pressure effects of empagliflozin in black patients with type 2 diabetes mellitus and hypertension. Circulation (2019) 139(18):2098–109. doi: 10.1161/CIRCULATIONAHA.118.036568

  • CrossRef
  • Google Scholar

• 71

  Sone H Kaneko T Shiki K Tachibana Y Pfarr E Lee J et al . Efficacy and safety of empagliflozin as add–on to insulin in Japanese patients with type 2 diabetes: A randomized, double–blind, placebo–controlled trial. Diabetes Obes Metab (2020) 22(3):417–26. doi: 10.1111/dom.13909

  • CrossRef
  • Google Scholar

• 72

  Rodbard HW Seufert J Aggarwal N Cao A Fung A Pfeifer M et al . Efficacy and safety of titrated canagliflozin in patients with type 2 diabetes mellitus inadequately controlled on metformin and sitagliptin. Diabetes Obes Metab (2016) 18(8):812–9. doi: 10.1111/dom.12684

  • CrossRef
  • Google Scholar

• 73

  Fonseca VA Ferrannini E Wilding JP Wilpshaar W Dhanjal P Ball G et al . Active– and placebo–controlled dose–finding study to assess the efficacy, safety, and tolerability of multiple doses of ipragliflozin in patients with type 2 diabetes mellitus. J Diabetes Complications (2013) 27(3):268–73. doi: 10.1016/j.jdiacomp.2012.11.005

  • CrossRef
  • Google Scholar

• 74

  Wilding JP Ferrannini E Fonseca VA Wilpshaar W Dhanjal P Houzer A . Efficacy and safety of ipragliflozin in patients with type 2 diabetes inadequately controlled on metformin: a dose–finding study. Diabetes Obes Metab (2013) 15(5):403–9. doi: 10.1111/dom.12038

  • CrossRef
  • Google Scholar

• 75

  Kashiwagi A Kazuta K Yoshida S Nagase I . Randomized, placebo–controlled, double–blind glycemic control trial of novel sodium–dependent glucose cotransporter 2 inhibitor ipragliflozin in Japanese patients with type 2 diabetes mellitus. J Diabetes Invest (2014) 5(4):382–91. doi: 10.1111/jdi.12156

  • CrossRef
  • Google Scholar

• 76

  Kashiwagi A Akiyama N Shiga T Kazuta K Utsuno A Yoshida S et al . Efficacy and safety of ipragliflozin as an add–on to a sulfonylurea in Japanese patients with inadequately controlled type 2 diabetes: results of the randomized, placebo–controlled, double–blind, phase III EMIT study. Diabetol Int (2015) 6(2):125–38. doi: 10.1007/s13340–014–0184–9

  • CrossRef
  • Google Scholar

• 77

  Kashiwagi A Kazuta K Goto K Yoshida S Ueyama E Utsuno A . Ipragliflozin in combination with metformin for the treatment of Japanese patients with type 2 diabetes: ILLUMINATE, a randomized, double–blind, placebo–controlled study. Diabetes Obes Metab (2015) 17(3):304–8. doi: 10.1111/dom.12331

  • CrossRef
  • Google Scholar

• 78

  Kashiwagi A Kazuta K Takinami Y Yoshida S Utsuno A Nagase I . Ipragliflozin improves glycemic control in Japanese patients with type 2 diabetes mellitus: the BRIGHTEN study: BRIGHTEN: double–blind randomized study of ipragliflozin to show its efficacy as monotherapy in T2DM patients. Diabetol Int (2015) 6(1):8–18. doi: 10.1007/s13340–014–0164–0

  • CrossRef
  • Google Scholar

• 79

  Kashiwagi A Shiga T Akiyama N Kazuta K Utsuno A Yoshida S et al . Efficacy and safety of ipragliflozin as an add–on to pioglitazone in Japanese patients with inadequately controlled type 2 diabetes: a randomized, double–blind, placebo–controlled study (the SPOTLIGHT study). Diabetol Int (2015) 6(2):104–16. doi: 10.1007/s13340–014–0182–y

  • CrossRef
  • Google Scholar

• 80

  Ishihara H Yamaguchi S Nakao I Okitsu A Asahina S . Efficacy and safety of ipragliflozin as add–on therapy to insulin in Japanese patients with type 2 diabetes mellitus (IOLITE): a multi–centre, randomized, placebo–controlled, double–blind study. Diabetes Obes Metab (2016) 18(12):1207–16. doi: 10.1111/dom.12745

  • CrossRef
  • Google Scholar

• 81

  Lu CH Min KW Chuang LM Kokubo S Yoshida S Cha BS . Efficacy, safety, and tolerability of ipragliflozin in Asian patients with type 2 diabetes mellitus and inadequate glycemic control with metformin: Results of a phase 3 randomized, placebo–controlled, double–blind, multicenter trial. J Diabetes Investig (2016) 7(3):366–73. doi: 10.1111/jdi.12422

  • CrossRef
  • Google Scholar

• 82

  Han KA Chon S Chung CH Lim S Lee KW Baik S et al . Efficacy and safety of ipragliflozin as an add–on therapy to sitagliptin and metformin in Korean patients with inadequately controlled type 2 diabetes mellitus: A randomized controlled trial. Diabetes Obes Metab (2018) 20(10):2408–15. doi: 10.1111/dom.13394

  • CrossRef
  • Google Scholar

• 83

  Shestakova MV Wilding JPH Wilpshaar W Tretter R Orlova VL Verbovoy AF . A phase 3 randomized placebo–controlled trial to assess the efficacy and safety of ipragliflozin as an add–on therapy to metformin in Russian patients with inadequately controlled type 2 diabetes mellitus. Diabetes Res Clin Pract (2018) 146:240–50. doi: 10.1016/j.diabres.2018.10.018

  • CrossRef
  • Google Scholar

• 84

  Kaku K Kadowaki T Seino Y Okamoto T Shirakawa M Sato A et al . Efficacy and safety of ipragliflozin in Japanese patients with type 2 diabetes and inadequate glycaemic control on sitagliptin. Diabetes Obes Metab (2021) 23(9):2099–108. doi: 10.1111/dom.14448

  • CrossRef
  • Google Scholar

• 85

  Rosenstock J Cefalu WT Lapuerta P Zambrowicz B Ogbaa I Banks P et al . Greater dose–ranging effects on A1C levels than on glucosuria with LX4211, a dual inhibitor of SGLT1 and SGLT2, in patients with type 2 diabetes on metformin monotherapy. Diabetes Care (2015) 38(3):431–8. doi: 10.2337/dc14–0890

  • CrossRef
  • Google Scholar

• 86

  Sykes AP O'Connor–Semmes R Dobbins R Dorey DJ Lorimer JD Walker S et al . Randomized trial showing efficacy and safety of twice–daily remogliflozin etabonate for the treatment of type 2 diabetes. Diabetes Obes Metab (2015) 17(1):94–7. doi: 10.1111/dom.12391

  • CrossRef
  • Google Scholar

• 87

  Sykes AP O'Connor–Semmes R Dobbins R Dorey DJ Lorimer JD Walker S et al . Randomized trial showing efficacy and safety of twice–daily remogliflozin etabonate for the treatment of type 2 diabetes. Diabetes Obes Metab (2015) 17(1):94–7. doi: 10.1111/dom.12391

  • CrossRef
  • Google Scholar

• 88

  DharMalingam M Aravind SR Thacker H Paramesh S Mohan B Chawla M et al . Efficacy and safety of remogliflozin etabonate, a new sodium glucose co–transporter–2 inhibitor, in patients with type 2 diabetes mellitus: a 24–week, randomized, double–blind, active–controlled trial. Drugs (2020) 80(6):587–600. doi: 10.1007/s40265–020–01285–0

  • CrossRef
  • Google Scholar

• 89

  Bailey CJ Gross JL Hennicken D Iqbal N Mansfield TA List JF et al . Dapagliflozin add–on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double–blind, placebo–controlled 102–week trial. BMC Med (2013) 11(43):1–10. doi: 10.1186/1741–7015–11–43

  • CrossRef
  • Google Scholar

• 90

  Strojek K Yoon KH Hruba V Sugg J Langkilde AM Parikh S et al . Dapagliflozin added to glimepiride in patients with type 2 diabetes mellitus sustains glycemic control and weight loss over 48 weeks: A randomized, double–blind, parallel–group, placebo–controlled trial. Diabetes Ther (2014) 5(1):267–83. doi: 10.1007/s13300–014–0072–0

  • CrossRef
  • Google Scholar

• 91

  Wilding JPH Woo V Rohwedder K Sugg J Parikh S . Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: Efficacy and safety over 2 years. Diabetes Obes Metab (2014) 16(2):124–36. doi: 10.1111/dom.12187

  • CrossRef
  • Google Scholar

• 92

  Jabbour SA Frías JP Ahmed A Hardy E Choi J Sjöström CD et al . Efficacy and safety over 2 years of exenatide plus dapagliflozin in the DURATION–8 study: A multicenter, double–blind, phase 3, randomized controlled trial. Diabetes Care (2020) 43(10):2528–36. doi: 10.2337/dc19–1350

  • CrossRef
  • Google Scholar

• 93

  Haering HU Merker L Christiansen AV Roux F Salsali A Kim G et al . Empagliflozin as add–on to metformin plus sulphonylurea in patients with type 2 diabetes. Diabetes Res Clin Pract (2015) 110(1):82–90. doi: 10.1016/j.diabres.2015.05.044

  • CrossRef
  • Google Scholar

• 94

  Kovacs CS Seshiah V Merker L Christiansen AV Roux F Salsali A et al . Empagliflozin as add–on therapy to pioglitazone with or without metformin in patients with type 2 diabetes mellitus. Clin Ther (2015) 37(8):1773–1788.e1771. doi: 10.1016/j.clinthera.2015.05.511

  • CrossRef
  • Google Scholar

• 95

  Roden M Merker L Christiansen AV Roux F Salsali A Kim G et al . Safety, tolerability and effects on cardiometabolic risk factors of empagliflozin monotherapy in drug–naïve patients with type 2 diabetes: A double–blind extension of a Phase III randomized controlled trial. Cardiovasc Diabetol (2015) 14:154. doi: 10.1186/s12933–015–0314–0

  • CrossRef
  • Google Scholar

• 96

  Haneda M Seino Y Inagaki N Kaku K Sasaki T Fukatsu A et al . Influence of renal function on the 52–week efficacy and safety of the sodium glucose cotransporter 2 inhibitor luseogliflozin in Japanese patients with type 2 diabetes mellitus. Clin Ther (2016) 38(1):66–88.e20. doi: 10.1016/j.clinthera.2015.10.025

  • CrossRef
  • Google Scholar

• 97

  Grunberger G Camp S Johnson J Huyck S Terra SG Mancuso JP et al . Ertugliflozin in patients with stage 3 chronic kidney disease and type 2 diabetes mellitus: the VERTIS RENAL randomized study. Diabetes Ther (2018) 9(1):49–66. doi: 10.1007/s13300–017–0337–5

  • CrossRef
  • Google Scholar

• 98

  Yale JF Bakris G Cariou B Nieto J David–Neto E Yue D et al . Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab (2014) 16(10):1016–27. doi: 10.1111/dom.12348

  • CrossRef
  • Google Scholar

• 99

  Perkovic V Jardine MJ Neal B Bompoint S Heerspink HJL Charytan DM et al . Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. New Engl J Med (2019) 380(24):2295–306. doi: 10.1056/NEJMoa1811744

  • CrossRef
  • Google Scholar

• 100

  Fioretto P Del Prato S Goldenberg R Giorgino F Reyner D Reyner D et al . Eficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (chronic kidney disease Stage 3A): the DERIVE Study. Diabetes Obes Metab (2018) 20(11):2532–40. doi: 10.1111/dom.13413

  • CrossRef
  • Google Scholar

• 101

  Pollock C Stefánsson B Reyner D Rossing P Sjöström CD Wheeler DC et al . Albuminuria–lowering effect of dapagliflozin alone and in combination with saxagliptin and effect of dapagliflozin and saxagliptin on glycaemic control in patients with type 2 diabetes and chronic kidney disease (DELIGHT): a randomised, double–blind, placebo–controlled trial. Lancet Diabetes Endocrinol (2019) 7(6):429–44. doi: 10.1016/S2213–858719()30086–5

  • CrossRef
  • Google Scholar

• 102

  Barnett AH Mithal A Manassie J Jones R Rattunde H Woerle HJ et al . Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double–blind, placebo–controlled trial. Lancet Diabetes Endocrinol (2014) 2(5):369–84. doi: 10.1016/S2213–858713()70208–0

  • CrossRef
  • Google Scholar

• 103

  Wanner C Inzucchi SE Lachin JM Fitchett D von Eynatten M Mattheus M et al . Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med (2016) 37(54):323–34. doi: 10.1056/NEJMoa1515920

  • CrossRef
  • Google Scholar

• 104

  Kashiwagi A Takahashi H Ishikawa H Yoshida S Kazuta K Utsuno A et al . A randomized, double–blind, placebo–controlled study on long–term efficacy and safety of ipragliflozin treatment in patients with type 2 diabetes mellitus and renal impairment: Results of the Long–Term ASP1941 Safety Evaluation in Patients with Type 2 Diabetes with Renal Impairment (LANTERN) study. Diabetes Obes Metab (2015) 17(2):152–60. doi: 10.1111/dom.12403

  • CrossRef
  • Google Scholar

• 105

  Cherney DZI Ferrannini E Umpierrez GE Peters AL Rosenstock J Carroll AK et al . Efficacy and safety of sotagliflozin in patients with type 2 diabetes and severe renal impairment. Diabetes Obes Metab (2021) 23(12):2632–42. doi: 10.1111/dom.14513

  • CrossRef
  • Google Scholar

• 106

  Bhatt DL Szarek M Pitt B Cannon CP Leiter LA McGuire DK et al . Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med (2021) 384(2):129–39. doi: 10.1056/NEJMoa2030186

  • CrossRef
  • Google Scholar

• 107

  Efficacy and Safety of Sotagliflozin Versus Placebo in Patients With Type 2 Diabetes Mellitus Not Currently Treated With Antidiabetic Therapy. Available at: https://clinicaltrials.gov/ct2/show/NCT02926937?term=NCT02926937&draw=2&rank=1.

  • Google Scholar

• 108

  Safety and Efficacy Study of Sotagliflozin on Glucose Control in Participants With Type 2 Diabetes, Moderate Impairment of Kidney Function, and Inadequate Blood Sugar Control (SOTA–CKD3). Available at: https://clinicaltrials.gov/ct2/show/NCT03242252?term=NCT03242252&draw=2&rank=1.

  • Google Scholar

• 109

  Efficacy and Bone Safety of Sotagliflozin 400 and 200 mg Versus Placebo in Participants With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control (SOTA–BONE). Available at: https://clinicaltrials.gov/ct2/show/NCT03386344?term=NCT03386344&draw=2&rank=1.

  • Google Scholar

• 110

  Efficacy and Safety of Sotagliflozin Versus Placebo in Patients With Type 2 Diabetes Mellitus on Background of Metformin. Available at: https://clinicaltrials.gov/ct2/show/NCT02926950?term=NCT02926950&draw=2&rank=1.

  • Google Scholar

• 111

  Efficacy and Safety of Sotagliflozin Versus Placebo and Empagliflozin in Participants With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control While Taking a DPP4 Inhibitor Alone or With Metformin (SOTA–EMPA). Available at: https://clinicaltrials.gov/ct2/show/NCT03351478?term=NCT03351478&draw=1&rank=1.

  • Google Scholar

• 112

  Efficacy and Safety of Sotagliflozin Versus Placebo in Participants With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control While Taking Insulin Alone or With Other Oral Antidiabetic Agents (SOTA–INS) . Available at: https://clinicaltrials.gov/ct2/show/NCT03285594?term=NCT03285594&draw=2&rank=1.

  • Google Scholar

• 113

  Efficacy and Safety of Sotagliflozin Versus Placebo in Participants With Type 2 Diabetes Mellitus on Background of Sulfonylurea Alone or With Metformin. Available at: https://clinicaltrials.gov/ct2/show/NCT03066830?term=NCT03066830&draw=2&rank=1.

  • Google Scholar

• 114

  Efficacy and Safety of Sotagliflozin Versus Glimepiride and Placebo in Participants With Type 2 Diabetes Mellitus That Are Taking Metformin Monotherapy (SOTA–GLIM). Available at: https://clinicaltrials.gov/ct2/show/NCT03332771?term=NCT03332771&draw=1&rank=1.

  • Google Scholar

• 115

  A 16 Weeks Study on Efficacy and Safety of Two Doses of Empagliflozin (BI 10773) (Once Daily Versus Twice Daily) in Patients With Type 2 Diabetes Mellitus and Preexisting Metformin Therapy. Available at: https://clinicaltrials.gov/ct2/show/NCT01649297?term=NCT01649297&draw=2&rank=1.

  • Google Scholar

• 116

  A Study of the Effects of Canagliflozin (JNJ–28431754) on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus (CANVAS–R). Available at: https://clinicaltrials.gov/ct2/show/NCT01989754?term=NCT01989754&draw=2&rank=1.

  • Google Scholar

• 117

  A Study of the Effects of Canagliflozin (JNJ–28431754) on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus (CANVAS–R) . Available at: https://clinicaltrials.gov/ct2/show/NCT01989754?term=NCT01989754&draw=2&rank=1.

  • Google Scholar

• 118

  Dapagliflozin Effects on Epicardial Fat. Available at: https://clinicaltrials.gov/ct2/show/NCT02235298?term=NCT02235298&draw=2&rank=1.

  • Google Scholar

• 119

  Kohan DE Fioretto P Tang W List JF . Long–term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. . Kidney Int (2014) 85(4):962–71. doi: 10.1038/ki.2013.356

  • CrossRef
  • Google Scholar

• 120

  Bode B Stenlof K Harris S Sullivan D Fung A Usiskin K et al . Long–term efficacy and safety of canagliflozin over 104 weeks in patients aged 55–80 years with type 2 diabetes. Diabetes Obes Metab (2015) 17(3):294–330. doi: 10.1111/dom.12428

  • CrossRef
  • Google Scholar

• 121

  Tanaka H Takano K Iijima H Maruyama N Hashimoto T Hashimoto T et al . Factors affecting canagliflozin–induced transient urine volume increase in patients with type 2 diabetes mellitus. Adv Ther (2017) 34(2):436–51. doi: 10.1007/s12325–016–0457–8

  • CrossRef
  • Google Scholar

• 122

  Moon JS Kim NH Na JO Jeong IK Lee SH Mok JO et al . Safety and effectiveness of empagliflozin in korean patients with type 2 diabetes mellitus: results from a nationwide post–marketing surveillance. Diabetes Metab J (2023) 47(1):82–91. doi: 10.4093/dmj.2021.0356

  • CrossRef
  • Google Scholar

• 123

  Inagaki N Nangaku M Sakata Y Sasaki K Mori–Anai K Iwasaki T et al . Real–world safety and effectiveness of canagliflozin treatment for type 2 diabetes mellitus in Japan: SAPPHIRE, a long–term, large–scale post–marketing surveillance. Adv Ther (2022) 39(1):674–91. doi: 10.1007/s12325–021–01984–4

  • CrossRef
  • Google Scholar

• 124

  Utsunomiya K Koshida R Kakiuchi S Senda M Fujii S Kurihara Y et al . Safety and effectiveness of tofogliflozin in Japanese patients with type 2 diabetes mellitus treated in real–world clinical practice: Results of a 36–month post–marketing surveillance study (J–STEP/LT). J Diabetes Investig (2021) 12(2):184–99. doi: 10.1111/jdi.13333

  • CrossRef
  • Google Scholar

• 125

  Maegawa H Tobe K Nakamura I Uno S . Real–world evidence for long–term safety and effectiveness of ipragliflozin in treatment–naive versus non–naive Japanese patients with type 2 diabetes mellitus: subgroup analysis of a 3–year post–marketing surveillance study (STELLA–LONG TERM). Diabetol Int (2021) 12(4):430–44. doi: 10.1007/s13340–021–00501–w

  • CrossRef
  • Google Scholar

• 126

  Lin DS Lee JK Chen WJ . Clinical adverse events associated with sodium–glucose cotransporter 2 inhibitors: A meta–analysis involving 10 randomized clinical trials and 71 553 individuals. J Clin Endocrinol Metab (2021) 106(7):2133–45. doi: 10.1210/clinem/dgab274

  • CrossRef
  • Google Scholar

• 127

  Menne J Dumann E Haller H Schmidt BMW . Acute kidney injury and adverse renal events in patients receiving SGLT2–inhibitors: A systematic review and meta–analysis. PloS Med (2019) 16(12):e1002983. doi: 10.1371/journal.pmed.1002983

  • CrossRef
  • Google Scholar

• 128

  Dutta D Jindal R Mehta D Khandelwal D Sharma M . Efficacy and safety of novel sodium glucose cotransporter–2 inhibitor remogliflozin in the management of type 2 diabetes mellitus: A systematic review and meta–analysis. Diabetes Metab Syndr (2021) 15(6):102315. doi: 10.1016/j.dsx.2021.102315

  • CrossRef
  • Google Scholar

• 129

  Mukai J Kanno S Kubota R . A literature review and meta–analysis of safety profiles of SGLT2 inhibitors in Japanese patients with diabetes mellitus. . Sci Rep (2021) 11(1):13472. doi: 10.1038/s41598–021–92925–2

  • CrossRef
  • Google Scholar

• 130

  Qiu M Ding LL Zhang M Zhou HR . Safety of four SGLT2 inhibitors in three chronic diseases: A meta–analysis of large randomized trials of SGLT2 inhibitors. Diabetes Vasc Dis Res (2021) 18(2):14791641211011016. doi: 10.1177/14791641211011016

  • CrossRef
  • Google Scholar

• 131

  Nakamura I Maegawa H Tobe K Uno S . Real–world evidence for long–term safety and effectiveness of ipragliflozin in Japanese patients with type 2 diabetes mellitus: final results of a 3–year post–marketing surveillance study (STELLA–LONG TERM). Expert Opin Pharmacother (2021) 22(3):373–87. doi: 10.1080/14656566.2020.1817388

  • CrossRef
  • Google Scholar