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Possible vascular and renal protective effects of sodium-glucose cotransporter 2 inhibitors

Possible vascular and renal protective effects of sodium-glucose cotransporter 2 inhibitors. Hidekatsu Yanai, MD, PhD, FACP National Center for Global Health and Medicine Kohnodai Hospital, Chiba, JAPAN. Effect and characteristics of sodium-glucose cotransporter 2 inhibitors (SGLT-2i).

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Possible vascular and renal protective effects of sodium-glucose cotransporter 2 inhibitors

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  1. Possible vascular and renal protective effects of sodium-glucose cotransporter 2 inhibitors Hidekatsu Yanai, MD, PhD, FACP National Center for Global Health and Medicine Kohnodai Hospital, Chiba, JAPAN

  2. Effect and characteristics of sodium-glucose cotransporter 2 inhibitors (SGLT-2i) Treatment with SGLT-2i Diabetic patients SGLT-2 SGLT-2 X glucose glucose Glomerulus Glomerulus Renal tubule Renal tubule Adverse effects ●Urinary tract infection ●Genital infection ●Dehydration ●Eczema

  3. Sodium-Glucose Cotransporter 2 Inhibitors: Possible Anti-Atherosclerotic Effects Beyond Glucose Lowering. Yanai H, et al. J Clin Med Res. 2016;8:10-4.

  4. Caloric loss by SGLT-2inhibition Plasma glucose Insulin secretion Osmotic diuretics by SGLT-2inhibition Body weight Visceral or body Fat Glucagon secretion ? Insulin sensitivity ? Blood pressure Inflammatory cytokines Adiponectin HDL-C TG Anti-atherosclerosis

  5. Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Metabolic Parameters in Patients With Type 2 Diabetes: A Chart-Based Analysis Katsuyama H, Yanai H, et al. J Clin Med Res. 2016;8:237-43.

  6. Characteristics of subjects (n＝50) (Katsuyama H, Yanai H, et al. J Clin Med Res 2016)

  7. Effects of 6 month-SGLT-2i treatment on metabolic parameters (Katsuyama H, Yanai H, et al. J Clin Med Res 2016)

  8. Correlation between changes in HbA1c levels and HbA1c levels at baseline (Katsuyama H, Yanai H, et al. J Clin Med Res 2016)

  9. Correlation between changes in ALT levels and ALT levels at baseline (Katsuyama H, Yanai H, et al. J Clin Med Res 2016)

  10. eGFR and effects of SGLT2i SGLT-2 glucose Glomerulus Proximal renal tubule Approximately 90% of SGLT2 is expressed in proximal renal tubules, therefore, the use of SGLT2i to patients with low eGFR was not recommended because of low efficacy.

  11. An Influence of the Estimated Glomerular Filtration Rate on Improvement in Metabolic Parameters by Sodium-Glucose Cotransporter 2 Inhibitors. Katsuyama H, Yanai H. J Clin Med Res. 2016;8:486-8.

  12. Characteristics of subjects (Katsuyama H, Yanai H. J Clin Med Res 2016)

  13. Influence of eGFRon improvement in HbA1c Low eGFR (n=26) 72±14 mL/min/1.73m2 High eGFR (n=22) 117±36 mL/min/1.73m2 *P < 0.05 vs. High eGFR **P < 0.001 vs. High eGFR Correlation between baseline eGFR and improvement in HbA1c NS r = -0.35 (P = 0.06) NS r = -0.36 (P = 0.06) (Katsuyama H, Yanai H. J Clin Med Res 2016)

  14. Influence of eGFRon improvement in body weight Low eGFR (n=26) 72±14 mL/min/1.73m2 High eGFR (n=22) 117±36 mL/min/1.73m2 (Katsuyama H, Yanai H. J Clin Med Res 2016)

  15. What Properties of Sodium-Glucose Cotransporter 2 Inhibitors Determine the Improvement in Hemoglobin A1c and Body Weight? Yanai H, et al. J Clin Med Res. 2017;9:446-448.

  16. Changes in HbA1c Changes in body Changes in HbA1c after 12 weeks in weight after after 12 weeks patients with 12 weeks renal insufficiency r P value r P value r P value Changes in HbA1c after 12 weeks ー ー 0.427 0.473 0.353 0.492 0.427 0.473 ー ー 0.977 0.004 Changes in body weight after 12 weeks Changes in HbA1c after 12 weeks in patients 0.353 0.492 0.977 0.004 ー ー with moderate renal insufficiency Maximal plasma cocentration -0.834 0.039 0.008 0.99 -0.112 0.833 SGLT2 inhibitory concentration 50% (IC50) -0.59 0.218 0.203 0.744 -0.036 0.945 IC50 adjusted by the lowest potency 0.639 0.172 -0.175 0.778 -0.016 0.977 (Potency to Inhibit SGLT2) (Potency to Inhibit SGLT2) x (Maximal plasma -0.931 0.007 -0.422 0.479 -0.162 0.76 concentration) Selectivity (IC50 for SGLT2 vs. IC50 for SGLT1) -0.156 0.768 0.876 0.051 0.669 0.146 Correlation between changes in HbA1c and body weight by SGLT2i and pharmacological properties of each SGLT2i Suzuki M, et al. J Pharmacol Exp Ther. 2012 Data from phase 3 research trials of each SGLT2i in Japan Nishiyama A,et al. Jpn Pharmacol Ther. 2015 (Yanai H, et al. J Clin Med Res. 2017)

  17. Correlation between changes in HbA1c by SGLT2i and pharmacological properties of each SGLT2i Changes in HbA1c Changes in body Changes in HbA1c after 12 weeks in weight after after 12 weeks patients with after 12 weeks renal insufficiency r P value r P value r P value Changes in HbA1c after 12 weeks ー ー 0.427 0.473 0.353 0.492 Changes in body weight after 12 weeks 0.427 0.473 ー ー 0.977 0.004 Changes in HbA1c after 12 weeks in patients 0.353 0.492 0.977 0.004 ー ー with moderate renal insufficiency Maximal plasma cocentration -0.834 0.039 0.008 0.99 -0.112 0.833 SGLT2 inhibitory concentration 50% (IC50) -0.59 0.218 0.203 0.744 -0.036 0.945 IC50 adjusted by the lowest potancy 0.639 0.172 -0.175 0.778 -0.016 0.977 (Potency to Inhibit SGLT2) (Potency to Inhibit SGLT2) x (Maximal plasma -0.931 0.007 -0.422 0.479 -0.162 0.76 concentration) Selectivity (IC50 for SGLT2 vs. IC50 for SGLT1) -0.156 0.768 0.876 0.051 0.669 0.146 The improvement in HbA1c by SGLT2i may depend on potency to inhibit SGLT2 (Yanai H, et al. J Clin Med Res 2017)

  18. Correlation between changes in body weight by SGLT2i and pharmacological properties of each SGLT2i Changes in HbA1c Changes in body after 12 weeks in Changes in HbA1c weight after patients with after 12 weeks 12 weeks renal insufficiency r P value r P value r P value Changes in HbA1c after 12 weeks ー ー 0.427 0.473 0.353 0.492 0.427 0.473 ー ー 0.977 0.004 Changes in body weight after 12 weeks Changes in HbA1c after 12 weeks in patients 0.353 0.492 0.977 0.004 ー ー with moderate renal insufficiency Maximal plasma cocentration -0.834 0.039 0.008 0.99 -0.112 0.833 SGLT2 inhibitory concentration 50% (IC50) -0.59 0.218 0.203 0.744 -0.036 0.945 IC50 adjusted by the lowest potancy 0.639 0.172 -0.175 0.778 -0.016 0.977 (Potency to Inhibit SGLT2) (Potency to Inhibit SGLT2) x (Maximal plasma -0.931 0.007 -0.422 0.479 -0.162 0.76 concentration) Selectivity (IC50 for SGLT2 vs. IC50 for SGLT1) -0.156 0.768 0.876 0.051 0.669 0.146 SGLT2i with a larger reduction of HbA1c in patients with renal insufficiency showed a larger reduction of body weight. Weight loss by SGLT2i may not depend on SGLT2. (Yanai H, et al. J Clin Med Res 2017)

  19. Correlation between changes in body weight by SGLT2i and pharmacological properties of each SGLT2i Changes in HbA1c Changes in body Changes in HbA1c after 12 weeks in weight after after 12 weeks patients with 12 weeks renal insufficiency r P value r P value r P value Changes in HbA1c after 12 weeks ー ー 0.427 0.473 0.353 0.492 0.427 0.473 ー ー 0.977 0.004 Changes in body weight after 12 weeks Changes in HbA1c after 12 weeks in patients 0.353 0.492 0.977 0.004 ー ー with moderate renal insufficiency Maximal plasma cocentration -0.834 0.039 0.008 0.99 -0.112 0.833 SGLT2 inhibitory concentration 50% (IC50) -0.59 0.218 0.203 0.744 -0.036 0.945 IC50 adjusted by the lowest potancy 0.639 0.172 -0.175 0.778 -0.016 0.977 (Potency to Inhibit SGLT2) (Potency to Inhibit SGLT2) x (Maximal plasma -0.931 0.007 -0.422 0.479 -0.162 0.76 concentration) Selectivity (IC50 for SGLT2 vs. IC50 for SGLT1) -0.156 0.768 0.876 0.051 0.669 0.146 SGLT2i with lower selectivity for SGLT2may show a larger reduction of body weight. Weight loss by SGLT2i cannot be explained by only SGLT2 inhibition. (Yanai H, et al. J Clin Med Res 2017)

  20. Prevention of cardiovascular event by SGLT2i

  21. EMPA-REG Trial CV event (Zinman B, et al. N Engl J Med 2015)

  22. EMPA-REG Trial CV death (Zinman B, et al. N Engl J Med 2015)

  23. EMPA-REG Trial Hospitalization for heart failure (Zinman B, et al. N Engl J Med 2015)

  24. Renal protective effects of SGLT2i

  25. Wanner C et al. N Engl J Med 2016;375:323-334. Wanner C et al. N Engl J Med 2016;375:323-334.

  26. Risk Comparison for Seven Renal Outcomes. Wanner C et al. N Engl J Med 2016;375:323-334. Worsening nephropathy39%↓ Progression to macroalbuminuria 38%↓ Doubling of serum creatinine44%↓ Initiation of renal-replacement55%↓

  27. The mechanisms for renal protection by SGLT2i Reduction of intra-glomerular pressure Novel mechanism

  28. Increased Hematocrit During Sodium-Glucose Cotransporter 2 Inhibitor Therapy Indicates Recovery of Tubulointerstitial Function in Diabetic Kidneys (Sano M, et al.J Clin Med Res 2016;8)

  29. A Possible Mechanism for Renoprotective Effect of Sodium-Glucose Cotransporter 2 Inhibitor: Elevation of Erythropoietin Production. Yanai H, et al. J Clin Med Res. 2017;9:178-179.

  30. Effects of SGLT2i on hematocrit and eGFR (Yanai H, Kastuyama H.J Clin Med Res 2017)

  31. Renal Function over Time. Wanner C et al. N Engl J Med 2016;375:323-334.

  32. Renal protective effect of erythropoietin in rats treated with puromycin which induces nephritis Without pre-treatment by erythropoietin Normal With pre-treatment by erythropoietin FP: foot process SD:slit diaphragm (Trend cell Biol, 457, 2007) (Eto N,et al. Kidney International 2007)

  33. Previous reports that proved renal protective effects of erythropoietin ●Chronic treatment with eythropoetin attenuated renal injury beyond hematopoiesis in the streptozotocin- induced diabetic rats.1 ●Treatment with the erythropoietin receptor activators protected podocytes from advanced glycation end- products (AGEs) -mediated damage, suggesting that early treatment with erythropoietin may help to prevent diabetic nephropathy.2 ●Erythropoietin ameliorates podocyte injury in advanced diabetic nephropathy in the db/db mouse.3 1. Toba H, et al. Eur J Pharmacol. 2009;612(1-3):106-114. 2. Ruester C, et al. Nephron Exp Nephrol. 2011;117(1):e21-30. 3. Loeffler I, et al. Am J Physiol Renal Physiol. 2013;305(6):F911-918.

  34. Effects of dapagliflozin on serum erythropoietin Dapagliflozin Placebo Hydrochlorothiazide (Lambers Heerspink HJ,et al. Diabetes Obes Metab. 2013)

  35. Effects of Six Kinds of Sodium-Glucose Cotransporter 2 Inhibitors on Metabolic Parameters, and Summarized Effect and Its Correlations With Baseline Data. Yanai H, et al. J Clin Med Res. 2017;9:605-612.

  36. Effects of 6 kinds of SGLT2i on metabolic parameters (Yanai H, et al. J Clin Med Res. 2017)

  37. (Yanai H, et al. J Clin Med Res. 2017)

  38. The most crucial determinant of change in each metabolic parameter by SGLT2i in baseline data (Yanai H, et al. J Clin Med Res. 2017)

  39. (Yanai H, et al. J Clin Med Res. 2017)

  40. The improvement in each metabolic parameter except for body weight by SGLT2i may depend on baseline data of each metabolic parameter (Yanai H, et al. J Clin Med Res. 2017)

  41. Summary ●SGLT2i improve body weight, blood pressure, liver function, uric acid, serum lipids, in addition to an improvement in glucose. ●The improvement in HbA1c by SGLT2i may depend on eGFR at baseline, however, weight loss by SGLT2i did not depend on eGFR at baseline. ●The correlation between pharmacological properties of SGLT2i between changes in HbA1c and body weight by SGLT2i suggested that the improvement in HbA1c depend on SGLT2 inhibition, however, reduction of body weight was not closely associated with SGLT2 inhibition.

  42. Summary ●The improvement in each metabolic parameter except for body weight by SGLT2i may depend on baseline data of each metabolic parameter. ●SGLT2i reduce CV events, especially, hospitalization for heart failure. ●Further studies should be performed to elucidate the effects of SGLT2i for coronary artery disease and stroke. ●SGLT2i have renal protective effect.

  43. Please submit your interesting works to our Journal, JEM!

  44. Thank you for your attention! National Center for Global Health and Medicine

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