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      SGLT2 Inhibitors as a Therapeutic Option for Diabetic Nephropathy

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          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.

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          Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications.

          Hiddo J.L. Heerspink, Bruce A. Perkins, David H. Fitchett … (2016)
          Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition also is associated with an acute, dose-dependent reduction in estimated glomerular filtration rate by ≈5 mL·min(-1)·1.73 m(-2) and ≈30% to 40% reduction in albuminuria. These effects mirror preclinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (estimated glomerular filtration rate 30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin, even though, by design, the hemoglobin A1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital infections, empagliflozin-treated patients had fewer serious adverse events, including a lower risk of acute kidney injury. In light of the EMPA-REG OUTCOME results, some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with type 2 diabetes mellitus who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease. With additional cardiorenal protection trials underway, sodium-related physiological effects of SGLT2 inhibitors and clinical correlates of natriuresis, such as the impact on blood pressure, heart failure, kidney protection, and mortality, will be a major management focus.
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            Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus.

            Hermann Koepsell, Ram Sharma, Neil Thomson … (2013)
            The Na-glucose cotransporter SGLT2 mediates high-capacity glucose uptake in the early proximal tubule and SGLT2 inhibitors are developed as new antidiabetic drugs. We used gene-targeted Sglt2 knockout (Sglt2(-/-)) mice to elucidate the contribution of SGLT2 to blood glucose control, glomerular hyperfiltration, kidney growth, and markers of renal growth and injury at 5 wk and 4.5 mo after induction of low-dose streptozotocin (STZ) diabetes. The absence of SGLT2 did not affect renal mRNA expression of glucose transporters SGLT1, NaGLT1, GLUT1, or GLUT2 in response to STZ. Application of STZ increased blood glucose levels to a lesser extent in Sglt2(-/-) vs. wild-type (WT) mice (∼300 vs. 470 mg/dl) but increased glucosuria and food and fluid intake to similar levels in both genotypes. Lack of SGLT2 prevented STZ-induced glomerular hyperfiltration but not the increase in kidney weight. Knockout of SGLT2 attenuated the STZ-induced renal accumulation of p62/sequestosome, an indicator of impaired autophagy, but did not attenuate the rise in renal expression of markers of kidney growth (p27 and proliferating cell nuclear antigen), oxidative stress (NADPH oxidases 2 and 4 and heme oxygenase-1), inflammation (interleukin-6 and monocyte chemoattractant protein-1), fibrosis (fibronectin and Sirius red-sensitive tubulointerstitial collagen accumulation), or injury (renal/urinary neutrophil gelatinase-associated lipocalin). SGLT2 deficiency did not induce ascending urinary tract infection in nondiabetic or diabetic mice. The results indicate that SGLT2 is a determinant of hyperglycemia and glomerular hyperfiltration in STZ-induced diabetes mellitus but is not critical for the induction of renal growth and markers of renal injury, inflammation, and fibrosis.
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              Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects.

              Hiddo J. L. Heerspink, Mehul Desai, Meg Jardine … (2017)
              Sodium-glucose cotransporter 2 inhibition with canagliflozin decreases HbA1c, body weight, BP, and albuminuria, implying that canagliflozin confers renoprotection. We determined whether canagliflozin decreases albuminuria and reduces renal function decline independently of its glycemic effects in a secondary analysis of a clinical trial in 1450 patients with type 2 diabetes receiving metformin and randomly assigned to either once-daily canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride uptitrated to 6-8 mg. End points were annual change in eGFR and albuminuria over 2 years of follow-up. Glimepiride, canagliflozin 100 mg, and canagliflozin 300 mg groups had eGFR declines of 3.3 ml/min per 1.73 m(2) per year (95% confidence interval [95% CI], 2.8 to 3.8), 0.5 ml/min per 1.73 m(2) per year (95% CI, 0.0 to 1.0), and 0.9 ml/min per 1.73 m(2) per year (95% CI, 0.4 to 1.4), respectively (P<0.01 for each canagliflozin group versus glimepiride). In the subgroup of patients with baseline urinary albumin-to-creatinine ratio ≥30 mg/g, urinary albumin-to-creatinine ratio decreased more with canagliflozin 100 mg (31.7%; 95% CI, 8.6% to 48.9%; P=0.01) or canagliflozin 300 mg (49.3%; 95% CI, 31.9% to 62.2%; P<0.001) than with glimepiride. Patients receiving glimepiride, canagliflozin 100 mg, or canagliflozin 300 mg had reductions in HbA1c of 0.81%, 0.82%, and 0.93%, respectively, at 1 year and 0.55%, 0.65%, and 0.74%, respectively, at 2 years. In conclusion, canagliflozin 100 or 300 mg/d, compared with glimepiride, slowed the progression of renal disease over 2 years in patients with type 2 diabetes, and canagliflozin may confer renoprotective effects independently of its glycemic effects.
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                Author and article information

                Contributors
                Joseph V. Moxon: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 18 May 2017
                Publication date Collection: May 2017
                Volume: 18
                Issue: 5
                Electronic Location Identifier: 1083
                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; matoba@ 123456jikei.ac.jp (K.M.); ms05-takeda@ 123456jikei.ac.jp (Y.T.); y.nagai@ 123456jikei.ac.jp (Y.N.); akamine-tm@ 123456igakuken.or.jp (T.A.); yokotat@ 123456jikei.ac.jp (T.Y.); kazu-utsunomiya@ 123456jikei.ac.jp (K.U.)
                [2 ]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@ 123456igakuken.or.jp
                Author notes
                [* ]Correspondence: daijika@ 123456jikei.ac.jp ; Tel.: +81-3-3433-1111; Fax: +81-3-3578-9753
                Article
                Publisher ID: ijms-18-01083
                DOI: 10.3390/ijms18051083
                PMC ID: 5454992
                PubMed ID: 28524098
                SO-VID: 846f8c4c-2f66-4614-bb0c-e7d961506036
                Copyright © © 2017 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 30 January 2017
                Date accepted : 15 May 2017
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: diabetic nephropathy,cardiovascular disease,sglt2 inhibitors
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: diabetic nephropathy, cardiovascular disease, sglt2 inhibitors

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