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Cardiovascular and kidney outcomes of combination therapy with sodium-glucose cotransporter-2 inhibitors and mineralocorticoid receptor antagonists in patients with type 2 diabetes and chronic kidney disease: A systematic review and network meta-analysis

  • Shunichiro Tsukamoto
    Affiliations
    Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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  • Ryutaro Morita
    Affiliations
    Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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  • Takayuki Yamada
    Correspondence
    Corresponding authors at: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan (Hiromichi Wakui), Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, A919 Scaife Hall 3550 Terrace Street, Pittsburgh, PA, 15261 USA. (Takayuki Yamada)
    Affiliations
    Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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  • Shingo Urate
    Affiliations
    Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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  • Kengo Azushima
    Affiliations
    Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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  • Kazushi Uneda
    Affiliations
    Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Department of Kampo Medicine, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu, Japan
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  • Ryu Kobayashi
    Affiliations
    Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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  • Tomohiko Kanaoka
    Affiliations
    Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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  • Hiromichi Wakui
    Correspondence
    Corresponding authors at: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan (Hiromichi Wakui), Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, A919 Scaife Hall 3550 Terrace Street, Pittsburgh, PA, 15261 USA. (Takayuki Yamada)
    Affiliations
    Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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  • Kouichi Tamura
    Affiliations
    Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Published:November 16, 2022DOI:https://doi.org/10.1016/j.diabres.2022.110161

      Abstract

      Aims

      Both sodium-glucose cotransporter-2 (SGLT-2) inhibitors and mineralocorticoid receptor antagonists (MRAs) have been shown to reduce cardiovascular (CV) event in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). However, little evidence pertains to the benefits of their combined use.

      Methods

      We systematically searched the PubMed, MEDLINE, EMBASE, and Cochrane Library databases through July 2022. We selected randomized controlled trials comparing SGLT-2 inhibitors, MRAs, or SGLT-2 inhibitor + MRA combination therapy, with placebo in patients with T2D and CKD. We performed a network meta-analysis to indirectly compare the treatments. The primary outcome was a composite of CV events.

      Results

      Eight studies were selected with 36,186 patients. The primary outcome was significantly improved in the combination therapy group compared with the other groups (RR [95% CI]; vs SGLT-2 inhibitors, 0.76 [0.60; 0.96]; vs MRAs, 0.66 [0.53; 0.82]; vs placebo, 0.58 [0.47; 0.73]). Additionally, the combination therapy was associated with a considerable reduction in the risk of hyperkalemia (RR vs MRA, 0.43 [0.23; 0.79]).

      Conclusion

      Combination of SGLT-2 inhibitors and MRAs potentially reduced CV events compared with SGLT-2 inhibitors or MRAs alone. This combination may be a candidate treatment strategy for patients with T2D and CKD.

      Keywords

      Abbreviations:

      T2D (type 2 diabetes), CKD (chronic kidney disease), ESKD (end-stage kidney disease), CV (cardiovascular), RAS (renin-angiotensin system), SGLT-2 (sodium-glucose cotransporter-2), MRA (mineralocorticoid receptor antagonist), PRISM (Preferred Reporting Items for Systematic Reviews and meta-Analyses), PROSPERO (International Prospective Register of Systematic Reviews), eGFR (estimated glomerular filtration rate), UACR (urinary albumin/creatinine ratio), Cr (creatinine), RCT (randomized controlled trial), MI (myocardial infarction), HF (heart failure), AE (adverse event), RR (risk ratio), CI (confidence interval)
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