SGLT2 Inhibitors as a Therapeutic Option for Diabetic Nephropathy

doi:10.3390/ijms18051083

Review

. 2017 May 18;18(5):1083.

doi: 10.3390/ijms18051083.

SGLT2 Inhibitors as a Therapeutic Option for Diabetic Nephropathy

Daiji Kawanami¹, Keiichiro Matoba², Yusuke Takeda³, Yosuke Nagai⁴, Tomoyo Akamine^{5

6}, Tamotsu Yokota⁷, Kazunori Sango⁸, Kazunori Utsunomiya⁹

Affiliations

¹ Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. daijika@jikei.ac.jp.
² Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. matoba@jikei.ac.jp.
³ Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. ms05-takeda@jikei.ac.jp.
⁴ Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. y.nagai@jikei.ac.jp.
⁵ Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. akamine-tm@igakuken.or.jp.
⁶ Diabetic Neuropathy Project, Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. akamine-tm@igakuken.or.jp.
⁷ Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. yokotat@jikei.ac.jp.
⁸ Diabetic Neuropathy Project, Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. sango-kz@igakuken.or.jp.
⁹ Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. kazu-utsunomiya@jikei.ac.jp.

PMID: 28524098
PMCID: PMC5454992
DOI: 10.3390/ijms18051083

Review

SGLT2 Inhibitors as a Therapeutic Option for Diabetic Nephropathy

Daiji Kawanami et al. Int J Mol Sci. 2017.

. 2017 May 18;18(5):1083.

doi: 10.3390/ijms18051083.

Authors

Daiji Kawanami¹, Keiichiro Matoba², Yusuke Takeda³, Yosuke Nagai⁴, Tomoyo Akamine^{5

6}, Tamotsu Yokota⁷, Kazunori Sango⁸, Kazunori Utsunomiya⁹

Affiliations

¹ Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. daijika@jikei.ac.jp.
² Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. matoba@jikei.ac.jp.
³ Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. ms05-takeda@jikei.ac.jp.
⁴ Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. y.nagai@jikei.ac.jp.
⁵ Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. akamine-tm@igakuken.or.jp.
⁶ Diabetic Neuropathy Project, Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. akamine-tm@igakuken.or.jp.
⁷ Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. yokotat@jikei.ac.jp.
⁸ Diabetic Neuropathy Project, Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. sango-kz@igakuken.or.jp.
⁹ Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. kazu-utsunomiya@jikei.ac.jp.

PMID: 28524098
PMCID: PMC5454992
DOI: 10.3390/ijms18051083

Abstract

Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD) worldwide. Glycemic and blood pressure (BP) control are important but not sufficient to attenuate the incidence and progression of DN. Sodium-glucose cotransporter (SGLT) 2 inhibitors are a new class of glucose-lowering agent suggested to exert renoprotective effects in glucose lowering-dependent and independent fashions. Experimental studies have shown that SGLT2 inhibitors attenuate DN in animal models of both type 1 diabetes (T1D) and type 2 diabetes (T2D), indicating a potential renoprotective effect beyond glucose reduction. Renoprotection by SGLT2 inhibitors has been demonstrated in T2D patients with a high cardiovascular risk in randomized controlled trials (RCTs). These favorable effects of SGLT2 inhibitors are explained by several potential mechanisms, including the attenuation of glomerular hyperfiltration, inflammation and oxidative stress. In this review article, we discuss the renoprotective effects of SGLT2 inhibitors by integrating experimental findings with the available clinical data.

Keywords: SGLT2 inhibitors; cardiovascular disease; diabetic nephropathy.

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Conflict of interest statement

The authors declare no conflicts of interest in association with this study.

Figures

**Figure 1**
Sodium–glucose cotransporter (SGLT) 2 inhibitors exert multiple effects on diabetic nephropathy (DN). These agents improve glomerular filtration and reduce extracellular matrix (ECM) production, oxidative stress and inflammation. These effects contribute to the reduction of renal fibrosis and albuminuria. CTGF: Connective tissue growth factor; ICAM-1: Intercellular adhesion molecule-1; MCP-1: Monocyte chemoattractant protein-1; NF-κB: Nuclear factor-κB; Nox4: NADPH oxidase 4; ROS: Reactive oxygen species; TGF-β: Transforming growth factor β.

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References

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1. Stratton I.M., Adler A.I., Neil H.A., Matthews D.R., Manley S.E., Cull C.A., Hadden D., Turner R.C., Holman R.R. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): Prospective observational study. BMJ. 2000;321:405–412. doi: 10.1136/bmj.321.7258.405. - DOI - PMC - PubMed
1. Wong M.G., Perkovic V., Chalmers J., Woodward M., Li Q., Cooper M.E., Hamet P., Harrap S., Heller S., MacMahon S., et al. Long-term benefits of intensive glucose control for preventing end-stage kidney disease: ADVANCE-ON. Diabetes Care. 2016;39:694–700. doi: 10.2337/dc15-2322. - DOI - PubMed
1. Goto A., Arah O.A., Goto M., Terauchi Y., Noda M. Severe hypoglycaemia and cardiovascular disease: Systematic review and meta-analysis with bias analysis. BMJ. 2013;347:f4533. doi: 10.1136/bmj.f4533. - DOI - PubMed
1. Abdul-Ghani M.A., DeFronzo R.A. Lowering plasma glucose concentration by inhibiting renal sodium-glucose cotransport. J. Intern. Med. 2014;276:352–363. doi: 10.1111/joim.12244. - DOI - PMC - PubMed

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[1] De Nicola L., Gabbai F.B., Liberti M.E., Sagliocca A., Conte G., Minutolo R. Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: Targeting the renal tubule in diabetes. Am. J. Kidney Dis. 2014;64:16–24. doi: 10.1053/j.ajkd.2014.02.010. - DOI - PubMed

[2] De Nicola L., Gabbai F.B., Liberti M.E., Sagliocca A., Conte G., Minutolo R. Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: Targeting the renal tubule in diabetes. Am. J. Kidney Dis. 2014;64:16–24. doi: 10.1053/j.ajkd.2014.02.010. - DOI - PubMed

[3] Stratton I.M., Adler A.I., Neil H.A., Matthews D.R., Manley S.E., Cull C.A., Hadden D., Turner R.C., Holman R.R. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): Prospective observational study. BMJ. 2000;321:405–412. doi: 10.1136/bmj.321.7258.405. - DOI - PMC - PubMed

[4] Stratton I.M., Adler A.I., Neil H.A., Matthews D.R., Manley S.E., Cull C.A., Hadden D., Turner R.C., Holman R.R. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): Prospective observational study. BMJ. 2000;321:405–412. doi: 10.1136/bmj.321.7258.405. - DOI - PMC - PubMed

[5] Wong M.G., Perkovic V., Chalmers J., Woodward M., Li Q., Cooper M.E., Hamet P., Harrap S., Heller S., MacMahon S., et al. Long-term benefits of intensive glucose control for preventing end-stage kidney disease: ADVANCE-ON. Diabetes Care. 2016;39:694–700. doi: 10.2337/dc15-2322. - DOI - PubMed

[6] Wong M.G., Perkovic V., Chalmers J., Woodward M., Li Q., Cooper M.E., Hamet P., Harrap S., Heller S., MacMahon S., et al. Long-term benefits of intensive glucose control for preventing end-stage kidney disease: ADVANCE-ON. Diabetes Care. 2016;39:694–700. doi: 10.2337/dc15-2322. - DOI - PubMed

[7] Goto A., Arah O.A., Goto M., Terauchi Y., Noda M. Severe hypoglycaemia and cardiovascular disease: Systematic review and meta-analysis with bias analysis. BMJ. 2013;347:f4533. doi: 10.1136/bmj.f4533. - DOI - PubMed

[8] Goto A., Arah O.A., Goto M., Terauchi Y., Noda M. Severe hypoglycaemia and cardiovascular disease: Systematic review and meta-analysis with bias analysis. BMJ. 2013;347:f4533. doi: 10.1136/bmj.f4533. - DOI - PubMed

[9] Abdul-Ghani M.A., DeFronzo R.A. Lowering plasma glucose concentration by inhibiting renal sodium-glucose cotransport. J. Intern. Med. 2014;276:352–363. doi: 10.1111/joim.12244. - DOI - PMC - PubMed

[10] Abdul-Ghani M.A., DeFronzo R.A. Lowering plasma glucose concentration by inhibiting renal sodium-glucose cotransport. J. Intern. Med. 2014;276:352–363. doi: 10.1111/joim.12244. - DOI - PMC - PubMed

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SGLT2 Inhibitors as a Therapeutic Option for Diabetic Nephropathy

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SGLT2 Inhibitors as a Therapeutic Option for Diabetic Nephropathy

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