Cosa aggiungono gli inibitori di SGLT2 in termini di nefro-protezione?

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1 Cosa aggiungono gli inibitori di SGLT2 in termini di nefro-protezione? Giuseppe Pugliese Dipartimento di Medicina Clinica e Molecolare Università di Roma "La Sapienza

2 Disclosure Il Prof. Giuseppe Pugliese dichiara di aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche: Partecipazioni a Congressi: Astra-Zeneca, Laboratori Guidotti, Sanofi, Takeda; Relazioni / moderazioni / partecipazioni a board retribuite: Astra-Zeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dome, Mylan, Sigma-Tau, Takeda. Il Prof. Giuseppe Pugliese dichiara altresì il proprio impegno ad astenersi, nell ambito dell evento, dal nominare, in qualsivoglia modo o forma, aziende farmaceutiche e/o denominazione commerciale e di non fare pubblicità di qualsiasi tipo relativamente a specifici prodotti di interesse sanitario (farmaci, strumenti, dispositivi medico-chirurgici, ecc.).

3 Agenda General considerations Treatment with SGLT2 inhibitors and renal outcomes Treatment with SGLT2 inhibitors in CKD patients Placing SGLT2 inhibitors in the therapeutic algorithm Mechanisms of nephroprotection with SGLT2 inhibitors

4 Domanda 1 Cosa aggiungono secondo voi gli SGLT2 inibitori in termini di nefro-protezione nel paziente diabetico? Opzioni di risposta A. offrono la possibilità di combinare la nefro-protezione con il controllo della glicemia B. rappresentano una possibile alternativa ad altri farmaci ad azione nefro-protettiva C. non aggiungono molto rispetto ad altri trattamenti quali i bloccanti del RAS D. possono colmare un vuoto nel nostro armamentario terapeutico

5 Unmet needs in diabetic nephropathy p=0.39 Gregg EW et al. N Engl J Med. 2014;370: p<0.001 p<0.001 * Adjusted for age, sex, and race/ethnicity Afkarian M et al. JAMA. 2016;316:

6 Unmet needs in diabetic nephropathy Cumulative survival (Ref.) Alb - /egfr (1.53, 1.87) 1.75 Alb + /egfr - (1.61, 1.91) 2.76 Alb - /egfr + (2.51, 3.03) Alb + /egfr + Kramer H et al. Diabetes Care. 2018;41: Cumulative survival (Ref.) 1.45 (1.33, 1.58) 1.58 (1.43, 1.75) 2.08 (1.88, 2.30) Years of observation Years of observation Penno G et al. Diabetologia. 2018; Jul 21

7 Mechanism of action of SGLT2 inhibitors Glucose flux (mg/ml) threshold splay filtered splay Plasma glucose (mmol/l) -40% Tm G glicosuria reabsorbed +20% 60 Abdul-Ghani MA & DeFronzo RA. EndocrPract. 2008;14:

8 HbA 1c - and egfr-dependent effect of SGLT2 inhibitors Pooled data from 9 phase III studies FDA Endocrinologic and Metabolic Drugs Advisory Committee: Dapagliflozin BMS

9 SGLTs in the kidney be a i i D it d a lia. n a i tal sidita I Segment 1 (and 2) proximal tubule età lia@ i c So idita a l al as a t e r u Reabsorption of 90-95% glucose ed crive c e di s (Na+:glucose = 1:1) E IES rega L Low affinity (Km=~2 mm) high capacity UG e si p P PE ginal P SE e ori U I Segment tubule ion a G e3rsproximal d a v rat e la a rep ever p va er ricreabsorption of 5-10% glucose i t i s P po a i or 40-60% of remaining glucose D (Na+:glucose = 2:1) High affinity (Km=~0.2 mm) low capacity ia. g o tol SGLT-2 SGLT-1 Bakris GL et al. Kidney Int. 2009;75:

10 Renal outcomes with SGLT2 inhibitors: empagliflozin The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) - Chronic Kidney Disease (CKD) Incident or worsening of nephropathy Post-hoc renal composite outcome * * doubling of serum creatinine, initiation of renal-replacement therapy, or death from renal disease Wanner C et al. N Engl J Med. 2016;375:

11 Renal outcomes with SGLT2 inhibitors: empagliflozin The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) - Chronic Kidney Disease (CKD) Renal outcomes Wanner C et al. N Engl J Med. 2016;375:

12 Renal outcomes with SGLT2 inhibitors: empagliflozin The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) - Chronic Kidney Disease (CKD) Change in egfr over 192 weeks Change in egfr from baseline to last measurement during treatment & follow-up Wanner C et al. N Engl J Med. 2016;375:

13 Renal outcomes with SGLT2 inhibitors: empagliflozin The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) - Chronic Kidney Disease (CKD) Change in ACR over 192 weeks by albuminuria categories ACR at baseline to last measurement during treatment and follow-up by albuminuria categories Cherney DZI et al. Lancet Diabetes Endocrinol. 2017;5:

14 Renal outcomes with SGLT2 inhibitors: empagliflozin The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) - Chronic Kidney Disease (CKD) Improvement in albuminuria status From micro to normoalbuminuria From macro to micro or normoalbuminuria Cherney DZI et al. Lancet Diabetes Endocrinol. 2017;5:

15 Renal outcomes with SGLT2 inhibitors: empagliflozin The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) - Chronic Kidney Disease (CKD) Change in egfr over 192 weeks by albuminuria categories Cherney DZI et al. Lancet Diabetes Endocrinol. 2017;5:

16 Renal outcomes with SGLT2 inhibitors: canagliflozin The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program CANVAS and CANVAS-Renal (CANVAS-R) Progression of albuminuria* Composite renal outcome * * >30% increase in albuminuria or change from either normo to micro or macroalbuminuria or from micro to macroalbuminuria * 40% reduction in egfr, initiation of renalreplacement therapy, or death from renal disease Neal B et al. N Engl J Med. 2017; Jun 12

17 Renal outcomes with SGLT2 inhibitors: canagliflozin The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program CANVAS and CANVAS-Renal (CANVAS-R) Composite renal outcome * * Doubling of serum creatinine, ESRD, or death from renal disease Perkovic V et al. Lancet Diabetes Endocrinol. 2018;6:

18 Renal outcomes with SGLT2 inhibitors: canagliflozin The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program CANVAS and CANVAS-Renal (CANVAS-R) Renal outcomes Perkovic V et al. Lancet Diabetes Endocrinol. 2018;6:

19 Renal outcomes with SGLT2 inhibitors: canagliflozin The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program CANVAS and CANVAS-Renal (CANVAS-R) Renal outcomes by subgroups Perkovic V et al. Lancet Diabetes Endocrinol. 2018;6:

20 Renal outcomes with SGLT2 inhibitors: canagliflozin The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program CANVAS and CANVAS-Renal (CANVAS-R) Change in egfr over time Perkovic V et al. Lancet Diabetes Endocrinol. 2018;6:

21 Renal outcomes with SGLT2 inhibitors: canagliflozin The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program CANVAS and CANVAS-Renal (CANVAS-R) Change in ACR over time and by albuminuria categories Perkovic V et al. Lancet Diabetes Endocrinol. 2018;6:

22 Renal outcomes with SGLT2 inhibitors: canagliflozin The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program CANVAS and CANVAS-Renal (CANVAS-R) From normo to microalbuminuria Improvement in albuminuria status From normo or micro to macroalbuminuria Perkovic V et al. Lancet Diabetes Endocrinol. 2018;6:

23 Renal outcomes with SGLT2 inhibitors: canagliflozin The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program CANVAS and CANVAS-Renal (CANVAS-R) ACR egfr Renal composite* Renal outcomes by egfr category Annual change from week 6/13 Canagliflozin Placebo HR (95% CI) All 0.33± ± (1.02, 1.35) 0.59 < ± ± (0.62, 2.09) 45-< ± ± (0.62, 1.48) 60-< ± ± (0.89, 1.29) > ± ± (1.05, 1.88) Patients with an event per 1000 patient-years Loss Preservation Canagliflozin Placebo HR (95% CI) All (0.47, 0.77) 0.59 < (0.29, 1.48) < (0.46, 1.31) 60-< (0.41, 0.84) > (0.25, 0.78) Interaction P value Interaction P value * 40% egfr reduction, ESRD, or death from renal disease Favors canagliflozin Favors placebo Neuen B et al. Circulation Jun 25

24 Maintenance of BP (and weight)-lowering effect in CKD patients ia. g o l eto Canagliflozin iab D di.it a n alia a i l Ita sidit à t cie talia@ o S idi a l l a as a e t r u ed crive c e di s E IES rega L UG e si p P PE ginal P SE e ori U I n a G ersio d a v rat e la a rep ever p va er ric i t i s P po Dia Cherney DZI et al. Kidney Int. 2018;93: Petrykiv S et al. Clin J Am Soc Nephrol. 2017;12: Neuen B et al. Circulation Jun 25

25 Mechanisms for maintenance of BP-lowering effect in CKD patients Chan CW & Tang SCW. Kidney Int. 2018;93:22 24

26 A. infezioni urinarie B. chetoacidosi C. acute kidney injury D. fratture Domanda 2 Qual è secondo voi il principale evento avverso che può compromettere l efficacia nefro-protettiva degli SGLT2 inibitori? Opzioni di risposta

27 Mechanisms for AKI under SGLT2 inhibition Hahn K et al. Nat Rev Nephrol. 2016;12:

28 Safety issues with SGLT2 inhibitors: empagliflozin The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) - Chronic Kidney Disease (CKD) Wanner C et al. N Engl J Med. 2016;375:

29 Safety issues with SGLT2 inhibitors: canagliflozin The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program CANVAS and CANVAS-Renal (CANVAS-R) Neal B et al. N Engl J Med. 2017;377:

30 Meta-analysis of RCTs AKI with SGLT2 inhibitors Meta-analysis of RCTs Mount Sinai CKD registry and Geisinger Health System cohort Tang H et al. Diabetes Obes Metab. 2017;19: Event N AKI OR (95% CI) 0.80 ( ) Zhang XL et al. J Am Heart Assoc. 2018;7:e FDA adverse event report system database P Nadkarni GN et al. Diabetes Care. 2017;40: Perlman A et al. Nutr Metab Cardiovasc Dis. 2017;27:

31 Therapeutic algorithm for type 2 diabetes CKD? ADA. Standard of Medical Care in Diabetes, 2018

32 Domanda 3 Quali studi ulteriori sono secondo voi necessari per legittimare l uso degli SGLT2 inibitori per la nefroprotezione nel paziente diabetico? Opzioni di risposta A. studi di confronto con farmaci ad azione nefroprotettiva B. studi di efficacia in cui l outcome renale sia l endpoint primario C. studi di sicurezza in pazienti con ridotta funzione renale D. studi di efficacia in prevenzione primaria

33 Ongoing trials with primary renal endpoints The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Anticipated targets: 4,401 randomized Event-driven Duration 5.5 years Primary endpoint: composite of ESRD, doubling of serum creatinine, and renal or CV death. Secondary endpoints: Renal composite of ESRD, doubling of serum creatinine, and renal death; HF composite of CV death and hospitalization for congestive heart failure; CV composite of CV death, nonfatal acute myocardial infarction or stroke hospitalization for congestive heart failure or unstable angina; CV death; All-cause death. Clinicaltrials.gov.

34 Population: Diabetic and nondiabetic pts. CKD stage 2-4 UACR >200 mg/g Anticipated targets: 4,000 randomized Event-driven Duration 45 months Ongoing trials with primary renal endpoints A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (Dapa-CKD) Dapagliflozin 10 mg Placebo Primary endpoint: composite of ESRD, 50% egfr decline, and renal or CV death. Secondary endpoints: Renal composite of ESRD, 50% egfr decline, and renal death; HF composite of CV death and hospitalization for congestive heart failure; All-cause death. Clinicaltrials.gov.

35 Mechanisms of renal protection with SGLT2 inhibitors 1 glomerular hyperfiltration 6 HIF 2 glucotoxicity 4 NHE3 3 H 2O, Na +, and uric acid excretion 5 ketonemia Vallon V & Thomson SC. Diabetologia. 2017;60:

36 Glomerular hyperfiltration in diabetes C SN SN Hyperfiltration in residual nephrons in late stages of diabetic nephropathy Cherney D et al. Circulation. 2014;129: SN Surviving nephrons reduced GFR SN X Lost nephrons

37 Reduction of glomerular hyperfiltration with SGLT2 inhibitors Cherney D et al. Circulation. 2014;129:

38 Reduction of glomerular hyperfiltration with SGLT2 inhibitors SNGPF P glom Vallon V & Thomson SC. Diabetologia. 2017;60: Heerspink IJL et al. Diabetes Obes Metab. 2013;15:

39 Complementary actions of SGLT2 inhibitors and RAS blockers Perkovic V et al. Curr Med Res Opin. 2015;12:

40 Na + reabsorption in the kidney GFR, AT-II, Norepinephrine Proximal convoluted tubule (55-65%) Na + co-transporters Na + /H + exchangers SGLT2 inhibitors Carbonic anhydrase inhibitors Flow-dependent Thick ascending limb of the loop of Henle (25-35%) Na + /K + /2Cl - co-transporters Loop diuretics Urine 1% Flow-dependent Distal convoluted tubule (5-7%) Na + /Cl - co-transporters Thiazide diuretics Aldosterone, ANP Collecting duct (2-4%) Na + channels Amiloride, triamterene, Aldosterone receptor blockers

41 Sustained increase in urinary glucose excretion with SGLT2 inhibitors Bolinder J et al. Diabetes Obes Metab. 2014;16:

42 Sustained reduction in plasma volume with SGLT2 inhibitors Heerspink IJL et al. Diabetes Obes Metab. 2013;15:

43 Increased urate excretion with SGLT2 inhibitors Qiu H et al. Diabetes Metab Res Rev. 2017;33:e2886

44 Loop diuretic sparing effect of SGLT2 inhibitors The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) Fitchett D et al. Eur Heart J. 2016;37:

45 Reduced chloride concentration and NKCC inhibition NKCC = Na-K-2Cl co-transporter Greger R et al. Kidney Int. 1987;31:

46 The thrifty substrate Ferrannini E et al. Diabetes Care. 2016; 39:

47 Shift in fuel energetics with SGLT2 inhibitors Mudaliar S et al. Diabetes Care. 2016; 39:

48 Hypoxia-dependent effects of SGLT2 inhibitors O Neill J et al. Am J Physiol Renal Physiol. 2015;309:F227 F234

49 Increased hematocrit with SGLT2 inhibitors Heerspink IJL et al. Diabetes Obes Metab. 2013;15:

50 Conclusions There is an unmet need for effective measures for nephroprotection in diabetic patients. Trials with SGLT2 inhibitors have shown promising effects of these agents on renal outcomes, including decrease of both albuminuria and egfr decline. Treatment with SGLT2 inhibitors in CKD patients is less effective in reducing blood glucose, but not blood pressure levels and appears equally effective in improving cardiovascular and renal outcomes. Safety concerns with respect to nephroprotection include increased risk of AKI, which is mainly related to volume depletion and may be prevented by appropriate management of diuretic therapy. Further studies, including the ongoing trials with primary renal endpoints, are required for recommending SGLT2 inhibitors as nephroprotective agents in diabetic (and non-diabetic) individuals. Multiple mechanisms seems to be involved in nephroprotection with SGLT2 inhibitors, including reduced glomerular hyperfiltration and glucose-toxicity, volume depletion, urate excretion, shift in fuel energetics, and hypoxia-dependent effects.