Association of Sodium-Glucose Cotransporter 2 Inhibitors with Osteomyelitis and Other Lower Limb Safety Outcomes in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomised Controlled Trials
Abstract
:1. Introduction
2. Methods
2.1. Search Strategy and Selection Criteria
2.2. Data Analysis
3. Results
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Population | Study Type | Dates | Intervention | Participants | Controls | Osteomyelitis RR (95% CI) | Peripheral Artery Disease RR (95% CI) | Ulcers RR (95% CI) | Fractures RR (95% CI) | Amputations RR (95% CI) | Symmetric Polineuropathy RR (95% CI) | Infections RR (95% CI) | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Akasaka et al., 2022 [21] | Japanese adults with T2DM and HFpEF aged ≥20 years | Randomised controlled trial | 2017–2019 | Ipragliflozin 25 mg + Ipragliflozin50 mg | 40 | 33 | NA | NA | NA | NA | NA | NA | 0.28 (0.01–6.57) |
Amin et al., 2015 (1)1(2)1(3)(4)(5)1(6)1(7)1(8)1 [22] | Adults with T2DM aged 18–70 years | Randomised controlled trial | 2010–2011 | Ertugliflozin 1 mg; Ertugliflozin 1 mg; Ertugliflozin 5 mg; Ertugliflozin 5 mg; Ertugliflozin 10 mg; Ertugliflozin 10 mg; Ertugliflozin 25 mg; Ertugliflozin 25 mg | 54 54 55 55 55 55 55 55 | 54 55 54 55 54 55 54 55 | NA NA NA NA NA NA NA NA | NA NA NA NA NA NA NA NA | NA NA NA NA NA NA NA NA | NA NA NA NA NA NA NA NA | NA NA NA NA NA NA NA NA | NA NA NA NA NA NA NA NA | NA NA 2.95 (0.12–70.77) 3.00 (0.12–72.08) NA NA NA NA |
Ando et al., 2021 [23] | Japanese adults with T2DM aged ≥20 years | Randomised controlled trial | 2015–2018 | Canagliflozin 100 mg | 20 | 20 | NA | NA | NA | NA | NA | 1.00 (0.07–14.90) | NA |
Bae et al., 2020 [24] | Korean adults with T2DM aged 19–80 years | Randomised controlled trial | 2019–2020 | Empagliflozin 10 mg + Empagliflozin25 mg2 | 60 | 59 | NA | NA | NA | NA | NA | 2.95 (0.12–71.01) | 2.95 (0.12–71.01) |
Barnett et al., 2014 [25] | Adults with T2DM and CKD aged ≥18 years | Randomised controlled trial | 2010–2012 | Empagliflozin 25 mg | 37 | 37 | NA | NA | NA | NE3 | NA | NA | NA |
Cannon et al., 2020 (1)(2) [4] | Adults with T2DM and ACVD aged ≥40 years | Randomised controlled trial | 2013–2019 | Ertugliflozin 5 mg; Ertugliflozin 15 mg | 2752 2747 | 2747 2747 | 1.87 (0.79–4.41) 1.38 (0.55–3.41) | 0.58 (0.36–0.93) 0.76 (0.49–1.18) | 1.09 (0.48–2.46) 1.64 (0.77–3.46) | 1.28 (0.69–2.36) 1.11 (0.59–2.10) | 1.20 (0.81–1.77) 1.27 (0.86–1.87) | 2.99 (0.81–11.05) 0.33 (0.03–3.20) | 1.34 (0.92–1.94) 1.70 (1.19–2.43) |
Carbone et al., 2020 [26] | Adults with T2DM and HFrEF aged ≥18 years | Randomised controlled trial | 2016–2018 | Canagliflozin 100 mg | 17 | 19 | NA | NA | NA | NE3 | NE3 | NA | NA |
Chehrehgosha et al., 2021 (1)(2) [27] | Iranian adults with T2DM and NAFLD aged 20–65 years | Randomised controlled trial | 2019–2020 | Empagliflozin 10 mg; Empagliflozin 10 mg | 35 35 | 37 34 | NA NA | NA NA | 0.35 (0.01–8.36) 0.32 (0.01–7.69) | NA NA | NA NA | NA NA | NA NA |
Dagogo-Jack et al., 2017 (1)(2) [28] | Adults with T2DM aged ≥18 years | Randomised controlled trial | 2014–2016 | Ertugliflozin 5 mg; Ertugliflozin 15 mg | 156 155 | 153 153 | 2.94 (0.12–71.68) NE3 | NA NA | NA NA | 0.98 (0.06–15.54) 0.33 (0.01–8.02) | NA NA | NA NA | 0.98 (0.06–15.54) 0.33 (0.01–8.02) |
Fioretto et al., 2018 [29] | Adults with T2DM and CKD 3A aged 18–74 years | Randomised controlled trial | 2015–2017 | Dapagliflozin 10 mg | 160 | 161 | 0.34 (0.01–8.17) | NA | NA | NE3 | NE3 | NA | 1.01 (0.06–15.95) |
Gallo et al., 2019 (1)(2) [30] | Adults with T2DM aged ≥18 years | Randomised controlled trial | 2013–2017 | Ertugliflozin 5 mg; Ertugliflozin 15 mg | 207 205 | 209 209 | 3.03 (0.12–73.92) NE3 | NA NA | NA NA | 0.34 (0.01–8.21) 0.34 (0.01-8.29) | 3.03 (0.12-73.92) 5.10 (0.25–105.52) | NA NA | 3.03 (0.12–73.92) 3.06 (0.13–74.64) |
Hollander et al., 2017 (1)(2) [31] | Adults with T2DM aged ≥18 years | Randomised controlled trial | 2013–2016 | Ertugliflozin 5 mg; Ertugliflozin 15 mg | 448 441 | 437 437 | NA NA | NA NA | NA NA | 0.33 (0.01–7.96) 1.98 (0.18–21.78) | 0.33 (0.01-7.96) 0.99 (0.06–15.79) | NA NA | 0.98 (0.06–15.55) 0.33 (0.01–8.09) |
Inagaki et al., 2016 [32] | Japanese adults with T2DM aged ≥20 years | Randomised controlled trial | 2014–2015 | Canagliflozin 100 mg | 76 | 70 | NA | NA | NA | 0.31 (0.01–7.42) | NA | NA | NA |
Isshiki et al., 2020 [33] | Japanese adults with T2DM aged 20–74 years | Randomised controlled trial | 2016–2019 | Dapagliflozin 5 mg4 + Dapagliflozin10 mg | 50 | 45 | NA | NA | NA | NA | NA | 0.30 (0.01–7.20) | 0.30 (0.01–7.20) |
Jensen et al., 2020 [34] | Adults with HFrEF aged 18–84 years5 | Randomised controlled trial | 2017–2020 | Empagliflozin 10 mg | 19 | 14 | NA | NA | NA | NA | NE3 | NA | NA |
Kaku et al., 2014 (1)1(2)(3)1 [35] | Japanese adults with T2DM aged 20–74 years | Randomised controlled trial | 2010–2012 | Tofogliflozin 10 mg; Tofogliflozin 20 mg; Tofogliflozin 40 mg | 59 60 59 | 57 57 57 | NA NA NA | NA NA NA | NA NA NA | NA 0.32 (0.01–7.62) NA | NA NA NA | NA NA NA | NA NA NA |
Kashiwagi et al., 2014 (1) [36] | Japanese adults with T2DM aged ≥20 years | Randomised controlled trial | 2010 | Ipragliflozin 50 mg | 62 | 68 | NA | NA | NA | NA | NA | NA | 1.65 (0.28–9.52) |
Kashiwagi et al., 2014 (2) [37] | Japanese adults with T2DM aged ≥20 years | Randomised controlled trial | 2010 | Ipragliflozin 50 mg | 166 | 77 | 1.40 (0.06–34.01) | NA | NA | NA | NA | NA | 2.34 (0.11–48.07) |
Katakami et al., 2020 [38] | Japanese adults with T2DM aged 30–74 years | Randomised controlled trial | 2016–2019 | Tofogliflozin 20 mg | 169 | 171 | NA | 3.04 (0.12–73.99) | NA | NA | NE3 | NA | NA |
Kawamori et al., 2018 [39] | Japanese adults with T2DM aged ≥20 years | Randomised controlled trial | 2015–2017 | Empagliflozin 10 mg + Empagliflozin25 mg | 182 | 93 | NA | NA | NA | 2.57 (0.12–52.95) | NE3 | NA | NA |
Kitazawa et al., 2020 [40] | Japanese adults with T2DM aged 20–74 years | Randomised controlled trial | 2017–2018 | Tofogliflozin 20 mg | 33 | 31 | NA | NA | NA | 2.82 (0.12–66.82) | NA | NA | NA |
Lambers Heerspink et al., 2013 [41] | Adults with T2DM aged 18–70 years | Randomised controlled trial | 2009–2010 | Dapagliflozin 10 mg | 24 | 51 | NA | NA | NA | NA | NA | NA | 6.24 (0.26–147.80) |
Lingvay et al., 2019 [42] | Adults with T2DM aged ≥18 years | Randomised controlled trial | 2017–2018 | Canagliflozin 300 mg6 + Canagliflozin 100 mg6 | 394 | 394 | 0.33 (0.01–8.16) | NA | 0.20 (0.01–4.15) | 2.00 (0.18–21.97) | NE3 | 2.00 (0.91–4.40) | 5.00 (0.59–42.60) |
Miller et al., 2018 (1)(2) [43] | Adults with T2DM aged ≥18 years | Randomised controlled trial | 2014–2016 | Ertugliflozin 5 mg + Sitagliptin 100 mg; Ertugliflozin 15 mg + Sitagliptin 100 mg | 98 96 | 97 97 | NA NA | NA NA | NA NA | NE3 NE3 | NE3 NE3 | NA NA | 0.33 (0.01–8.00) 0.34 (0.01–8.17) |
Nassif et al., 2019 [44] | Adults with HFrEF aged >185 | Randomised controlled trial | 2016–2019 | Dapagliflozin 10 mg | 81 | 85 | NA | NA | NA | NA | NE3 | NA | NA |
Neal et al., 2017 [7] | Adults with T2DM and ACVD aged ≥30 years OR Adults with T2DM and ≥2 CV risk factors aged ≥50 years | Randomised controlled trial | 2009–2017 | Canagliflozin 100 mg + Canagliflozin 300 mg | 5795 | 4347 | 0.94 (0.44–2.00) | 2.12 (1.38–3.25) | 2.27 (1.63–3.16) | 1.20 (0.92–1.57) | 1.97 (1.53–2.54) | 1.48 (1.11–1.97) | 1.51 (1.19–1.91) |
Palau et al., 2022 [45] | Adults with HFrEF aged >18 years5 | Randomised controlled trial | 2019–2021 | Dapagliflozin 10 mg | 16 | 13 | NA | NA | NA | NA | NE3 | NA | NA |
Perkovic et al., 2019 [46] | Adults with T2DM and CKD aged ≥30 years | Randomised controlled trial | 2014–2018 | Canagliflozin 100 mg | 2202 | 2199 | 1.27 (0.58–2.79) | 1.27 (0.58–2.79) | 1.31 (1.00–1.72) | 1.50 (0.72–3.10) | 1.11 (0.79–1.55) | 0.83 (0.59–1.17) | 0.91 (0.65–1.27) |
Pollock et al., 2019 (1)(2) [47] | Adults with T2DM and CKD aged ≥18 years | Randomised controlled trial | 2015–2018 | Dapagliflozin 10 mg + Saxagliptin 2.5 mg; Dapagliflozin 10 mg | 155 145 | 148 148 | NA NA | NA NA | NA NA | 0.19 (0.01–3.95) 0.20 (0.01–4.22) | 2.87 (0.12–69.79) 3.06 (0.13–74.55) | NA NA | 2.87 (0.12–69.79) NE3 |
Pratley et al., 2017 (1)(2)(3)(4) [48] | Adults with T2DM aged ≥18 years | Randomised controlled trial | 2014–2016 | Ertugliflozin 5 mg; Ertugliflozin 15 mg; Ertugliflozin 5 mg + Sitagliptin 100 mg; Ertugliflozin 15 mg + Sitagliptin 100 mg | 250 248 243 245 | 247 247 247 247 | NA NA NA NA | NA NA NA NA | NA NA NA NA | NE3 NE3 NE3 NE3 | NE3 2.99 (0.12–72.99) NE3 NE3 | NA NA NA NA | NE3 2.99 (0.12–72.99) NE3 3.02 (0.12–73.88) |
Rau et al., 2021 [49] | Adults with T2DM aged 18–84 years | Randomised controlled trial | 2017–2019 | Empagliflozin 10 mg | 22 | 22 | NA | NA | NA | NE3 | NA | NA | NA |
Rosenstock et al., 2012 (1)1(2) [50] | Adults with T2DM aged ≥18 years | Randomised controlled trial | 2008–2010 | Dapagliflozin 5 mg; Dapagliflozin 10 mg | 141 140 | 139 139 | NA NA | NA NA | NA NA | NA NE3 | NA NA | NA NA | NA NA |
Sargeant et al., 2022 (1)(2)(3)(4) [51] | Adults with T2DM and BMI ≥25 kg/m2 aged 30–75 years | Randomised controlled trial | 2017–2019 | Empagliflozin 25 mg; Empagliflozin 25 mg; Empagliflozin 25 mg + ERD; Empagliflozin 25 mg + ERD | 17 17 17 17 | 17 17 17 17 | NA NA NA NA | NA NA NA NA | NA NA NA NA | NA NA NA NA | NE3 NE3 NE3 NE3 | NA NA NA NA | NA NA NA NA |
Schumm-Draeger et al., 2014 (1)1(2) [52] | Adults with T2DM aged 18–77 years | Randomised controlled trial | 2010–2011 | Dapagliflozin 5 mg; Dapagliflozin 10 mg | 100 199 | 101 101 | NA NA | NA NE3 | NA NA | NA NE3 | NA NA | NA NA | NA NA |
Sone et al., 2019 (1)(2) [53] | Japanese adults with T2DM aged 20–74 years | Randomised controlled trial | 2015–2018 | Empagliflozin 10 mg; Empagliflozin 25 mg | 89 90 | 90 90 | NA NA | NA NA | NA NA | 0.34 (0.01–8.16) 0.33 (0.01–8.08) | NE3 NE3 | NA NA | 0.34 (0.01–8.16) 1.00 (0.06–15.74) |
Spertus et al., 2022 [54] | Adults with HF aged ≥18 years5 | Randomised controlled trial | 2020–2021 | Canagliflozin 100 mg | 66 | 59 | NA | NA | NA | NA | NE3 | NA | NA |
Takashima et al., 2018 [55] | Japanese adults with T2DM and CKD aged 20–80 years | Randomised controlled trial | 2016–2017 | Canagliflozin 100 mg | 21 | 21 | NA | NA | NA | NA | NE3 | NA | NA |
Torimoto et al., 2019 [56] | Japanese adults with T2DM aged 18–79 years | Randomised controlled trial | 2015–2018 | Canagliflozin 100 mg | 17 | 17 | NA | NA | 0.33 (0.01–7.65) | NA | NA | 0.33 (0.01–7.65) | NA |
Wheeler et al., 2021 [57] | Adults with proteinuric CKD aged ≥18 years5 | Randomised controlled trial | 2017–2020 | Dapagliflozin 10 mg | 1455 | 1451 | NA | NA | NA | NA | 0.92 (0.58–1.45) | NA | NA |
Wiviott et al., 2019 [6] | Adults with T2DM and ACVD or multiple CV risk factors aged ≥40 years OR Men with T2DM and ≥1 CV risk factor aged ≥55 years OR Women with T2DM and ≥1 CV risk factor aged ≥60 years | Randomised controlled trial | 2013–2018 | Dapagliflozin 10 mg | 8582 | 8578 | 0.70 (0.40–1.22) | 0.97 (0.68–1.37) | 1.05 (0.58–1.90) | 1.07 (0.64–1.79) | 1.09 (0.84–1.40) | 0.75 (0.26–2.16) | 0.86 (0.70–1.07) |
Yang et al., 2018 [58] | Asian adults with T2DM aged ≥18 years | Randomised controlled trial | 2014–2016 | Dapagliflozin 10 mg | 139 | 133 | NA | NA | NA | NA | NA | 0.32 (0.01–7.76) | NA |
Yang et al., 2015 (1)1(2) [59] | Asian adults with T2DM aged ≥18 years | Randomised controlled trial | 2010–2013 | Dapagliflozin 5 mg; Dapagliflozin 10 mg | 147 152 | 145 145 | NA NA | NA NA | NA NA | NA 1.91 (0.17–20.81) | NA NA | NA NA | NA NA |
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Nani, A.; Carrara, F.; Paulesu, C.M.E.; Dalle Fratte, C.; Padroni, M.; Enisci, S.; Bilancio, M.C.; Romio, M.S.; Bertuzzi, F.; Pintaudi, B. Association of Sodium-Glucose Cotransporter 2 Inhibitors with Osteomyelitis and Other Lower Limb Safety Outcomes in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. J. Clin. Med. 2023, 12, 3958. https://doi.org/10.3390/jcm12123958
Nani A, Carrara F, Paulesu CME, Dalle Fratte C, Padroni M, Enisci S, Bilancio MC, Romio MS, Bertuzzi F, Pintaudi B. Association of Sodium-Glucose Cotransporter 2 Inhibitors with Osteomyelitis and Other Lower Limb Safety Outcomes in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. Journal of Clinical Medicine. 2023; 12(12):3958. https://doi.org/10.3390/jcm12123958
Chicago/Turabian StyleNani, Alessandro, Federica Carrara, Chiara Maria Eleonora Paulesu, Chiara Dalle Fratte, Matteo Padroni, Silvia Enisci, Maria Concetta Bilancio, Maria Silvia Romio, Federico Bertuzzi, and Basilio Pintaudi. 2023. "Association of Sodium-Glucose Cotransporter 2 Inhibitors with Osteomyelitis and Other Lower Limb Safety Outcomes in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomised Controlled Trials" Journal of Clinical Medicine 12, no. 12: 3958. https://doi.org/10.3390/jcm12123958
APA StyleNani, A., Carrara, F., Paulesu, C. M. E., Dalle Fratte, C., Padroni, M., Enisci, S., Bilancio, M. C., Romio, M. S., Bertuzzi, F., & Pintaudi, B. (2023). Association of Sodium-Glucose Cotransporter 2 Inhibitors with Osteomyelitis and Other Lower Limb Safety Outcomes in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. Journal of Clinical Medicine, 12(12), 3958. https://doi.org/10.3390/jcm12123958