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

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

The KID-ney behind the curtain

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;53:875-883. Bakris GL, et al. Kidney Int. 2009;75(12):1272-1277. Rahmoune H, et al. Diabetes. 2005;54(12):3427-3434.

EMPAREG-Outcome

EMPA-REG - 14%

EMPA-REG

All Cause Mortality Bblockers Statins Aspirin Empaglifozin - 36% -30% - 22% -32% Lancet 1986 4 S 1994 ISIS-2 EmpaREG

Primary MACE Outcome CV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke Patients with an event (%) 20 18 16 14 12 10 8 6 4 2 Hazard ratio 0.86 (95% CI, 0.75-0.97) p <0.0001 for noninferiority p = 0.0158 for superiority Placebo Canagliflozin 0 0 1 2 3 4 5 6 No. of patients Placebo Canagliflozin Years since randomization 4347 4153 2942 1240 1187 1120 789 5795 5566 4343 2555 2460 2363 1661 Intent-to-treat analysis Neal B. et al N Engl J Med 2017 June 12. doi: 10.1056/NEJMoa1611925

All-Cause Mortality Patients with an event (%) 20 18 16 14 12 10 8 6 4 2 Hazard ratio 0.87 (95% CI, 0.74-1.01) Placebo Canagliflozin 0 No. of patients Placebo Canagliflozin 0 1 2 3 4 5 6 Years since randomization 4347 4279 3119 1356 1328 1292 924 5795 5723 4576 2761 2710 2651 1904 Intent-to-treat analysis

Hospitalization for Heart Failure Patients with an event (%) 20 18 16 14 12 10 8 6 4 2 Hazard ratio 0.67 (95% CI, 0.52-0.87) Placebo Canagliflozin 0 No. of patients Placebo Canagliflozin 0 1 2 3 4 5 6 Years since randomization 4347 4198 3011 1274 1236 1180 829 5795 5653 4437 2643 2572 2498 1782 Intent-to-treat analysis

CV Death or Hospitalization for Heart Failure Patients with an event (%) 20 18 16 14 12 10 8 6 4 2 No. of patients Placebo Canagliflozin Hazard ratio 0.78 (95% CI, 0.67-0.91) 0 0 1 2 3 4 5 6 Years since randomization Placebo Canagliflozin 4347 4202 3015 1281 1242 1184 831 5795 5655 4442 2647 2577 2503 1782 Intent-to-treat analysis

Key Efficacy Outcomes in the CANVAS Program Hazard ratio (95% CI) CV death, nonfatal myocardial infarction, or nonfatal stroke p <0.0001 noninferiority p = 0.0158 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 0.5 1.0 2.0 Favors Canagliflozin Favors Placebo

Amputations All amputations (n = 187) Event rate per 1000 patient-years Canagliflozin Placebo 6.3 3.4 1.97 (1.41-2.75) Minor amputation (71%) 4.5 2.4 1.94 (1.31-2.88) Toe 3.4 2.2 Transmetatarsal 1.0 0.3 Major amputation (29%) 1.8 0.9 2.03 (1.08-3.82) Ankle 0.04 0.07 Below-knee 1.2 0.6 Above-knee 0.6 0.2 Hazard ratio (95% CI) 0.25 0.5 1.0 2.0 4.0 8.0 Favors Canagliflozin Favors Placebo

Fractures Adjudicated low-trauma fractures CANVAS Program (Heterogeneity p = 0.003) Event rate per 1000 patient-years Canagliflozin Placebo Hazard ratio (95% CI) 12 9.2 1.23 (0.99 1.52) CANVAS (n = 271) 13 8.3 1.56 (1.18 2.06) CANVAS-R (n = 108) 7.9 10 0.76 (0.52 1.12) All adjudicated fractures CANVAS Program (Heterogeneity p = 0.005) 15 12 1.26 (1.04 1.52) CANVAS (n = 350) 17 11 1.55 (1.21 1.97) CANVAS-R (n = 146) 11 13 0.86 (0.62 1.19) 0.25 0.5 1.0 2.0 4.0 8.0 Favors Canagliflozin Favors Placebo

- 39%

- 51%

- 46 %

FUEL SHIFT Hypothesis

EMPAGLIFOZIN: a new CV agent with antihyperglycemic effect

egfr (CKD-EPI) over 192 weeks Adjusted mean (SE) egfr (ml/min/1.73m 2 ) 78 76 74 72 70 68 Placebo Empagliflozin 10 mg Empagliflozin 25 mg 66 Baseline 4 12 28 52 66 80 94 108 122 136 150 164 178 192 No. analyzed Placebo 2323 2295 2267 2205 2121 2064 1927 Week 1981 1763 1479 1262 1123 977 731 448 Empagliflozin 10 mg 2322 2290 2264 2235 2162 2114 2012 2064 1839 1540 1314 1180 1024 785 513 Empagliflozin 25 mg 2322 2288 2269 2216 2156 2111 2006 2067 1871 1563 1340 1207 1063 838 524 No. in follow-up for adverse/outcome events Total 7020 7020 6996 6931 6864 6765 6696 6651 6068 5114 4443 3961 3488 2707 1703 N Engl J Med 2016; 375:323-334

Change in Albumin:Creatinine Ratio (UACR) Percent Change in UACR per Albuminuria Class (inset) Geometric mean UACR with 95% CI (mg/g) 50 45 40 35 30 25 20 15 10 No. of patients Placebo Canagliflozin 0% 10% 20% 30% 40% 50% Placebo 0 1 2 Normo Micro Macro 9% 34% 36% Canagliflozin 3 Years since randomization Mean % difference 18% (95% CI, 16 to 20) 4 5 6 4084 3775 2556 753 652 594 618 5500 5103 3565 1689 1541 1408 1534 Mixed model for repeated measures (MMRM) analysis Excluding those below detection level

Progression of Albuminuria Patients with an event (%) 100 90 80 70 60 50 40 30 20 10 0 Hazard ratio 0.73 (95% CI, 0.67-0.79) Placebo Canagliflozin 0 1 2 3 4 5 6 Years since randomization No. of patients Placebo Canagliflozin 3819 3096 1690 724 626 548 303 5196 4475 2968 1730 1528 1354 775 Intent-to-treat analysis

Regression of Albuminuria Patients with an event (%) 100 90 80 70 60 50 40 30 20 10 0 No. of patients Placebo Canagliflozin Hazard ratio 1.70 (95% CI, 1.51-1.91) 0 1 2 3 4 5 6 Years since randomization Placebo Canagliflozin 1257 913 426 163 144 123 59 1679 1009 518 276 227 198 112 Intent-to-treat analysis

Composite of 40% Reduction in egfr, End-stage Renal Disease, or Renal Death Patients with an event (%) No. of patients Placebo 20 18 16 14 12 10 Canagliflozin 8 6 4 2 0 4347 5795 Hazard ratio 0.60 (95% CI, 0.47-0.77) 4227 5664 3029 4454 Events (n) 40% egfr reduction 239 End-stage renal disease/renal death 21 0 1 2 3 4 5 6 Years since randomization 1274 2654 1229 2576 1173 2495 Placebo Canagliflozin 819 1781 Intent-to-treat analysis

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

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

Vasodilatazione A afferente Vasocostrizione A efferente SGLT2i ACEi TGF RAS

Applied physics model In-flow/out-flow pressure regulator for gas SGLT2 inhibitor RAAS blocker Cherney D et al. Circulation 2014;129:587-597

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

Occhio ai Nefrologi!!!