The Anticipated Renoprotective Effects of Sodium-glucose Cotransporter 2 Inhibitors

Abstract

Sodium-glucose cotransporter 2 (SGLT2), which is specifically expressed on the apical side of proximal tubular cells, is involved in the reabsorption of most of the glucose filtered by the glomeruli, and its inhibitors are gaining publicity as potent antihyperglycemic drugs. In some clinical trials, SGLT2 inhibitors exerted cardiovascular and kidney protective effects, which appeared to be partly independent of the original glucose-lowering effect. SGLT2 inhibitors have both direct and indirect renoprotective effects. The direct effects involve the suppression of hyperplasia/hypertrophy, inflammation, and fibrosis in the proximal tubular cells, utilization of ketone bodies, restored tubuloglomerular feedback, decreased oxygen consumption, improvement in anemia, and preconditioning against ischemia/reperfusion. The indirect effects involve a reduction in insulin levels and resistance, uric acid concentration, body weight, and blood pressure. However, safety concerns remain, including consequences of an enhanced glucose load in the lower nephron, leg amputation, bone fractures, and therapeutic efficacy in patients with advanced chronic kidney disease.

Keywords: diabetic kidney disease; final common pathway; sodium-glucose cotransporter 2 (SGLT2) inhibitors; tubuloglomerular feedback (TGF).

Figure 1.

Glucose reabsorption under normoglycemia (modified from 2). Under normoglycemia, -97% of the filtered glucose is reabsorbed by SGLT2 in the early proximal tubules (S1, S2). With the use of SGLT2 inhibitors, SGLT1 in the late proximal tubules (S3) reabsorbs glucose instead. Numbers in parentheses show reabsorption rates with the use of SGLT2 inhibitors. SGLT: sodium-glucose cotransporter Vallon V. The proximal tubule in the pathophysiology of the diabetic kidney. AJP Regul Integr Comp Physiol 300: R1009-R1022, 2011.

Figure 2.

Mean changes in HbA1c and eGFR from the baseline in the placebo and dapagliflozin groups (modified from 3). A: Mean changes in HbA1c from the baseline during the trial. Differences between the placebo and dapagliflozin groups were not significant because each group included both CKDG3a and CKDG3b patients. B: HbA1c Differences from placebo by baseline CKD stages 3A and 3B at 24 weeks. C: Mean changes in eGFR from the baseline during the trial. eGFR: estimated glomerular filtration rate, CKD: chronic kidney disease 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 85: 962-971, 2014.

Figure 3.

Renal outcome and renal function over time in the EMPA-REG OUTCOME trial (modified from 5). A: Kaplan-Meier analysis of a prespecified renal composite outcome (incident and worsening nephropathy). B: Kaplan-Meier analysis of a post-hoc renal composite outcome (doubling of serum creatinine level, initiation of renal-replacement therapy, or death from renal disease). The inset shows the data on an expanded y axis. C: Adjusted mean eGFR over a period of 192 weeks. D: Adjusted mean eGFR at the baseline, the last measurement during treatment, and follow-up. The difference at follow-up was smaller in both the 10 mg and 25 mg empagliflozin groups than in the placebo group by 4.7 mL/min/1.73 m² (p<0.001). eGFR: estimated glomerular filtration rate Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 375: 323-334, 2016.

Figure 4.

Renal outcomes in the integrated CANVAS program (modified from 6). A: Kaplan-Meier analysis of progression of albuminuria. B: Kaplan-Meier analysis of a renal composite outcome (40% reduction in eGFR, requirement for renal-replacement therapy, or death from renal causes). The inset shows the data on an expanded y axis. eGFR: estimated glomerular filtration rate Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377: 644-657, 2017.

Figure 5.

Energy metabolism in cardiomyocytes and renal tubular cells. Increased free fatty acids (FFAs) and decreased insulin/glucagon ratio promote production of β-hydroxybutyrate (β-HB) in the liver. Cardiomyocytes and renal tubular cells take up circulating β-HB as a fuel source for ATP, which suppresses the degradation of fatty acids and glucose (broken lines). AcAc: acetoacetate, Ox Phos: oxidative phosphorylation Ferrannini E, Mark M, Mayoux E. CV protection in the EMPAREG OUTCOME trial: a “Thrifty Substrate” hypothesis. Diabetes Care 39: 1108-1114, 2016.

Figure 6.

Postulated tubuloglomerular feedback (TGF) mechanisms (modified from 15). A: Under physiological conditions, TGF signaling controls afferent arteriole tone to maintain GFR. Transient increases in GFR cause the macula densa to sense the increase in distal tubular Na⁺ concentration and GFR is eventually decreased via TGF. B: Under chronic hyperglycemia, Na⁺ and glucose reabsorption by SGLT2 is promoted and TGF is impaired. In other words, in spite of increased GFR, the macula densa detects reduced distal tubular Na⁺ concentration. By this mechanism, afferent arterioles unsuitably dilate and GFR becomes elevated. C: SGLT2 inhibition results in interrupted Na⁺ and glucose reabsorption, leading to increased Na⁺ delivery to the macula densa. This allows afferent arterioles to constrict appropriately, restores TGF, and normalizes GFR. GFR: glomerular filtration rate, SGLT2: sodium-glucose cotransporter 2 Cherney DZI, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 129: 587-597, 2014.

Figure 7.

Mean change in haematocrit, haemoglobin, reticulocyte count and erythropoietin over the course of the study in placebo dapagliflozin, and hydrochlorothiazide groups. Data are reported as mean (±95% CI). Because of an extreme outlier, the median concentrations (25th and 75th percentile) in erythropoietin over time are reported in the figure. Excluding the outlier and calculating the mean value provided a similar picture (data not shown). P: placebo, D: dapagliflozin, H: hydrochlorothiazide. IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON PERMISSIONS@WILEY.COM OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSIONS' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER. Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab 15: 853-862, 2013. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/dom.12127