Paolo Fornengo SCDU Medicina Interna 3 AOU Città della Salute e della Scienza di Torino

Transcription

1 Paolo Fornengo SCDU Medicina Interna 3 AOU Città della Salute e della Scienza di Torino

2 The KID-ney behind the curtain

3 Altered Renal Glucose Control in Diabetes Gluconeogenesis is increased in postprandial and postabsorptive states in patients with Type 2 DM Renal contribution to hyperglycemia 3-fold increase relative to patients without diabetes Glucose reabsorption Increased SGLT-2 expression and activity in renal epithelial cells from patients with diabetes vs. normoglycemic individuals Tubular uptake of glucose is important in the detrimental effects of diabetes as well as in the glucose homeostasis Marsenic O. Am J Kidney Dis. 2009;53: Bakris GL, et al. Kidney Int. 2009;75(12): Rahmoune H, et al. Diabetes. 2005;54(12):

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11 EMPAREG-Outcome

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22 EMPA-REG - 14%

23 EMPA-REG

24 All Cause Mortality Bblockers Statins Aspirin Empaglifozin - 36% -30% - 22% -32% Lancet S 1994 ISIS-2 EmpaREG

25 Primary MACE Outcome CV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke Patients with an event (%) Hazard ratio 0.86 (95% CI, ) p < for noninferiority p = for superiority Placebo Canagliflozin No. of patients Placebo Canagliflozin Years since randomization Intent-to-treat analysis Neal B. et al N Engl J Med 2017 June 12. doi: /NEJMoa

26 All-Cause Mortality Patients with an event (%) Hazard ratio 0.87 (95% CI, ) Placebo Canagliflozin 0 No. of patients Placebo Canagliflozin Years since randomization Intent-to-treat analysis

27 Hospitalization for Heart Failure Patients with an event (%) Hazard ratio 0.67 (95% CI, ) Placebo Canagliflozin 0 No. of patients Placebo Canagliflozin Years since randomization Intent-to-treat analysis

28 CV Death or Hospitalization for Heart Failure Patients with an event (%) No. of patients Placebo Canagliflozin Hazard ratio 0.78 (95% CI, ) Years since randomization Placebo Canagliflozin Intent-to-treat analysis

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30 Key Efficacy Outcomes in the CANVAS Program Hazard ratio (95% CI) CV death, nonfatal myocardial infarction, or nonfatal stroke p < noninferiority p = superiority CV death Nonfatal myocardial infarction Nonfatal stroke Hospitalization for heart failure CV death or hospitalization for heart failure All-cause mortality Progression of albuminuria Renal composite Favors Canagliflozin Favors Placebo

31 Amputations All amputations (n = 187) Event rate per 1000 patient-years Canagliflozin Placebo ( ) Minor amputation (71%) ( ) Toe Transmetatarsal Major amputation (29%) ( ) Ankle Below-knee Above-knee Hazard ratio (95% CI) Favors Canagliflozin Favors Placebo

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33 Fractures Adjudicated low-trauma fractures CANVAS Program (Heterogeneity p = 0.003) Event rate per 1000 patient-years Canagliflozin Placebo Hazard ratio (95% CI) ( ) CANVAS (n = 271) ( ) CANVAS-R (n = 108) ( ) All adjudicated fractures CANVAS Program (Heterogeneity p = 0.005) ( ) CANVAS (n = 350) ( ) CANVAS-R (n = 146) ( ) Favors Canagliflozin Favors Placebo

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46 FUEL SHIFT Hypothesis

47 EMPAGLIFOZIN: a new CV agent with antihyperglycemic effect

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50 egfr (CKD-EPI) over 192 weeks Adjusted mean (SE) egfr (ml/min/1.73m 2 ) Placebo Empagliflozin 10 mg Empagliflozin 25 mg 66 Baseline No. analyzed Placebo Week Empagliflozin 10 mg Empagliflozin 25 mg No. in follow-up for adverse/outcome events Total N Engl J Med 2016; 375:

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52 Change in Albumin:Creatinine Ratio (UACR) Percent Change in UACR per Albuminuria Class (inset) Geometric mean UACR with 95% CI (mg/g) No. of patients Placebo Canagliflozin 0% 10% 20% 30% 40% 50% Placebo Normo Micro Macro 9% 34% 36% Canagliflozin 3 Years since randomization Mean % difference 18% (95% CI, 16 to 20) Mixed model for repeated measures (MMRM) analysis Excluding those below detection level

53 Progression of Albuminuria Patients with an event (%) Hazard ratio 0.73 (95% CI, ) Placebo Canagliflozin Years since randomization No. of patients Placebo Canagliflozin Intent-to-treat analysis

54 Regression of Albuminuria Patients with an event (%) No. of patients Placebo Canagliflozin Hazard ratio 1.70 (95% CI, ) Years since randomization Placebo Canagliflozin Intent-to-treat analysis

55 Composite of 40% Reduction in egfr, End-stage Renal Disease, or Renal Death Patients with an event (%) No. of patients Placebo Canagliflozin Hazard ratio 0.60 (95% CI, ) Events (n) 40% egfr reduction 239 End-stage renal disease/renal death Years since randomization Placebo Canagliflozin Intent-to-treat analysis

56 Renal Outcomes Summary Canagliflozin compared to placebo Induced sustained lowering of albuminuria Prevented progression in albuminuria Induced regression in albuminuria Reduced renal function loss events Conclusion These data suggest a potential renoprotective effect of canagliflozin treatment in patients with type 2 diabetes at high CV risk on top of ACE/ARBs

57 Adjusted mean difference from placebo in empaglifozin group Change from baseline egfr 4.7 ml/min/1.73 m 2 Assuming a decline in egfr of 4 ml/min/1.73 m 2 Delaying the need for dialysis by approximately 1 yr

58 Vasodilatazione A afferente Vasocostrizione A efferente SGLT2i ACEi TGF RAS

59 Applied physics model In-flow/out-flow pressure regulator for gas SGLT2 inhibitor RAAS blocker Cherney D et al. Circulation 2014;129:

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61 Per il paziente diabetico di tipo 2 a rischio cardiovascolare; per il paziente diabetico con iniziale nefropatia

62 Occhio ai Nefrologi!!!