Sodium glucose cotransporter 2 (sglt2) inhibitors and the effect on the heart and chronic kidney disease.

1. Sweet Pee: Do Sodium–glucose co-transporter 2
(SGLT2) inhibitors have renal protective effects?
Moh’d Sharshir, M.D.
Assistant Professor of Medicine
Section, Nephrology
Tulane University School of Medicine

2. Disclosure
I have NO financial disclosure or conflicts of interest with the presented
material in this presentation

3. Introduction
• Diabetes is a global health emergency with 425
million people affected in the year 2017 and a
projection for 629 million by 2045.
• Half develop diabetic kidney disease, and its
prevalence is rising progressively in concert with
the overall diabetes epidemic, largely driven by
type 2 diabetes.
ESRD incidence is increasing because of DM
Adjusted prevalence of ESRD in the US 1996-2014
Alicic RZ, Rooney MT, Tuttle KR: Diabetic kidney disease: Challenges, progress, and possibilities. Clin J Am Soc Nephrol 12: 2032–2045, 2017 2016 Annual Data Report, Vol 2, ESRD, Ch 1 Fig 1.16

4. Introduction
• Type 2 diabetes mellitus (T2DM) is a major risk factor for the development
of cardiovascular (CV) and renal disease and is a key determinant of
hospitalizations, morbidity, and mortality.
Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes: JACC state-of-the-art review. J Am Coll Cardiol. 2018 Oct;72(15):1845–55.

5. Diabetic CKD + Cardiovascular Disease =
Hospitalization + Death
2016 Annual Data Report, Vol 1, CKD, Ch 3

6. Am J Kidney Dis. 2012;59(1):75-83)
Relative risks of major complications of chronic kidney
disease based upon a continuous meta-analysis
Levey AS, de Jong PE, Coresh J, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies
Conference report. Kidney Int 2010; 80:17. Copyright © 2010.

7. Introduction
• Until recently, the pharmacotherapy of T2DM was characterized by limited
direct beneficial CV or renal effects, with a range of deleterious side effects.

8. Stratton IM, et al. BMJ 2000; 321: 405–412.

11. Normal Glucose Reabsorption in the Kidney

12. SGLT2 is a high capacity, low-affinity transporter that is
expressed almost exclusively in the initial convoluted portion (S1
segment) of the proximal tubule, which accounts for 90% of the
reabsorbed glucose.
Residual glucose is reabsorbed by SLGT1, a low-capacity, high-
affinity transporter, at the end of the pars convoluta and pars
recta (S2/S3 segments) of the proximal tubule.

13. Zelniker, T.A. et al. J Am Coll Cardiol. 2018;72(15):1845–55

14. Normal Glucose Reabsorption in the Kidney
• The first identified nonselective SGLT1/SGLT2i, phlorizin, was isolated
from the root bark of apple trees in 1835.
• However, the high doses required to lower circulating glucose cause
severe diarrhea secondary to the inhibition of SGLT1 in the gut.
• SGLT2is have been shown to reduce glycosylated hemoglobin only by
approximately 0.5% to 1.0% in patients with T2DM.

15. Normal Glucose Reabsorption in the Kidney
• FDA has approved 4 SGLT2i for clinical use:
 Canagliflozin (Invokana):
 Dapagliflozin (Farxiga):
 Empagliflozin (Jardiance):
 Ertugliflozin (Steglatro):
• A fifth combined SGLT1 and 2 inhibitor, Sotagliflozin (Zynquista), is in
clinical development.

39. Zelniker and Braunwald, Cardiac Effects of SGLT2

46. Figure 1. morphology of human proximal tubule cell (HK2) after exposure/treatment (24hrs) with
normal (5mM)/ high glucose (33mM), k-LC (25μM) and Empagliflozin (500nM).

47. Figure 2. Effect of high glucose (33mM), k-FLC (25μM) and Empagliflozin (500nM)
exposure/treatment (24/48 hrs) on cytotoxicity and viability of HK2 cells.

48. Figure 3. Effect of high glucose (33mM), k-FLC (25μM) and Empagliflozin (500nM)
exposure/treatment (24hrs) on the apoptosis of HK2 cells.

49. Figure 5. Effect of high glucose (33mM), k-FLC (25μM) and Empagliflozin (500nM) exposure/treatment (24hrs) on
the gene expression of LCN2, KIM1 (HAVCR1) and IL6 in HK2 cells.

50. Figure 6. Expression of PeNOS/TeNOS protein in HK2 cells exposed with high glucose (HG,
33mM), free light chain (k-LC) and treated with Empagliflozin (500nM).

51. Figure 8. Empagliflozin restores HG induced down-regulation of SLC34A1.

52. Extraglycemic Effects of SGLT2 Inhibitors