The clinical landscape of managing patients with CKD: Where are we - PowerPoint PPT Presentation

The clinical landscape of managing patients with CKD: Where are we now and what can we expect? David Cherney, MD University of Toronto Toronto, Canada OFFICIAL WCN 2019 SPONSORED LUNCH SYMPOSIUM April 15, 2019 - Melbourne, Australia

The The Cli Clinical nical Land Landsca scape pe of M of Manag anaging ing CKD: CKD: Wh Wher ere e Ar Are e We We No Now w an and Wh d What at Ca Can n We We Ex Expe pect ct WCN - PACE 2019 David Cherney, MD CM, PhD, FRCP(C) Associate Professor of Medicine, University of Toronto Clinician Scientist, Division of Nephrology, UHN Director, Renal Physiology Laboratory, UHN Scientist, Toronto General Hospital Research Institute

Spe Speak aker er disc disclosu losure re Relationships with commercial entities: • Consulting / honoraria: Boehringer Ingelheim, Lilly, Janssen, Merck, AstraZeneca, Mitsubishi-Tanabe, Sanofi, • Clinical trials: CREDENCE, TRANSLATE, BETWEEN, DIAMOND, DAPA-CKD, SCORED, EMPA-CKD, INDORSE, ERADICATE-HF

Obje Objectives ctives • Hemodynamic effects of sodium glucose cotransport- 2 (SGLT2) inhibitors • Effects of SGLT2 inhibitors in non-diabetic CKD • Future trials

SGLT2 inhibition SGLT2, sodium – glucose co-transporter 2 Heerspink//Cherney HJ, et al. Circulation 2016;134:752 – 772

The “ Tubular Hypothesis ” : Normal Physiology Heerspink//Cherney. Circulation 2016

The “ Tubular Hypothesis ” : Diabetes and Hyperfiltration Heerspink//Cherney. Circulation 2016

The “ Tubular Hypothesis ” : Diabetes and SGLT2 Inhibition Heerspink//Cherney. Circulation 2016

SNGF SNGFR R and the a and the afferent arter fferent arteriole iole Kidokoro et al. ADA (abstract) 2018

In vivo imaging of A.A. change before and after empagliflozin Before medication 2hrs after medication Efferent A. Efferent A. G G Afferent A. Afferent A. Red: BSA-Alexa594 Courtesy: Kidokoro//Kashihara. American Diabetes Association Meeting – Saturday June 23, 2018

SGLT2 SGLT2 inhibi inhibition tion and th and the role e role of aden of adenosi osine ne Kidokoro et al. ADA (abstract) 2018

The alteration of SNGFR by empagliflozin under A1aR antagonist AA p = 0.99 * P = 0.0011 * P = 0.01 G Before medication AA G 30 min after medication Red: BSA-Alexa594 Courtesy: Kidokoro//Kashihara. American Diabetes Association Meeting – Saturday June 23, 2018

Afferent Efferent Afferent Efferent Pharmacological Haemodynamic effects and clinical actions: implications: SGLT2 inhibition A • Decreased intraglomerular pressure due to increased afferent resistance in T1D-H patients Afferent constriction • Decreased hyperfiltration • Decreased intraglomerular pressure due to B decreased efferent resistance RAAS blockade • Decreased hyperfiltration Efferent dilation • Proven renal protection in clinical trials • Normalisation of intraglomerular pressure due to SGLT2 inhibition and increased afferent and decreased efferent RAAS blockade resistance? C • Potential for additive intraglomerular pressure Afferent constriction and reduction? Efferent dilation • Potential for long-term renal protection? Skrtić //Cherney. Diabetologia 2014;57:2599 – 2602

SGLT2 inhibition SGLT2 inhibition 40%↓ eGFR, ESRD, Renal death 1.5% vs. 2.8% HR 0.53 (0.43-0.66) P<0.001 Wanner C, et al. N Engl J Med 2016;375:323 – 334 Neil et al. NEJM June 12, 2017 Wiviott et al. N Engl J Med Nov 2018

SGLT SGLT2 2 Inhibito Inhibitors rs – Non Non-Diab Diabet etic ic Co Cond ndition itions

Renal protection in non-diabetic kidney disease? Pilot data in patients with FSGS Rajasekeran//Cherney. AJP Renal 2018

Ren Renal al fun funct ction, ion, stru struct ctur ure: e: sub subto tota tall lly nep nephrec hrectomiz tomized ed (SNx SNx) ) Sprag Sprague ue-Dawley Dawley ra rats ts • No effect: GFR INULIN , ERPF PAH , proteinuria Rajasekeran//Cherney. AJP Renal 2018

E MPA -K IDNEY is an phase III, randomised, double-blind, placebo- controlled outcome trial Event driven: study continues until ≥ 1070 primary outcome events accrue 2-3 months 1 month Empagliflozin 10 mg + standard of care* Follow-up Placebo run-in visit Placebo + standard of care* End of treatment Months -2 0 2 6 12 +1 Every 6 months thereafter, Screening* Randomisation (1:1) until required number of Double-blind events has occurred N=~5000 *Single RAS inhibition in clinical appropriate dose and management of CV risk factors and other existing comorbidities incl. hypertension and diabetes ClinicalTrials.gov NCT03594110 (all accessed July 2018)

Both CVOTs and dedicated renal outcomes trials with SGLT2 inhibitors will generate data on renal endpoints Trial Patient cohorts N Endpoints DELIGHT 1 Dapagliflozin / 460 Primary: Percentage change in HbA 1c , UACR dapagliflozin + saxagliptin / Secondary: Proportion of patients achieving 30% reduction in UACR, body weight, FPG, seated SBP placebo 1:1:1 DECLARE 2 Dapagliflozin / placebo 1:1 17,150 Primary: MACE non-inferiority and then superiority of co-primary endpoints of MACE and hospitalisation for heart failure or CV death Secondary: all-cause mortality; renal composite endpoint (sustained ≥40% decrease in eGFR to eGFR <60 mL/min/1.73m 2 and/or ESRD and/or renal or CV death) CREDENCE 3 Canagliflozin / placebo 1:1 4200 Primary: Composite renal and CV endpoint (ESRD, doubling of serum creatinine, renal or CV death) Secondary: 5P-MACE (CV death, non-fatal MI or non-fatal stroke, hospitalisation for CHF, hospitalization for unstable angina), renal composite endpoint (ESRD, doubling of serum creatinine, renal death), all-cause mortality DAPA-HF 4 Dapagliflozin / placebo 1:1 4500 Primary: Composite CV endpoint (CV death, hospitalization for HF or urgent HF visit) (HFrEF) Secondary: CV death or hospitalization for HF, total HF hospitalizations and CV death events, KCCQ, renal composite (≥50% sustained decline in eGFR, ESRD, renal death), all-cause mortality Primary: Composite renal endpoint (≥50% sustained decline in eGFR, ESRD, CV or renal death) DAPA-CKD 5 Dapagliflozin / placebo 1:1 4000 Secondary: Renal composite (≥50% sustained decline in eGFR, ESRD, renal death), CV death or hospitalization for HF, all-cause (CKD) mortality 2018 2019 2020 VERTIS- EMPA-KIDNEY DELIGHT CREDENCE DECLARE DAPA-HF DAPA-CKD CV 1. NCT02547935. Available at https://clinicaltrials.gov/ct2/show/NCT02547935 ; 2. NCT01730534. Available at https://clinicaltrials.gov/ct2/show/NCT01730534; 3. NCT02065791. Available at https://clinicaltrials.gov/ct2/show/NCT02065791; 4. NCT03036124. Available at https://clinicaltrials.gov/ct2/show/NCT03036124; 5. NCT03036150. Available at https://clinicaltrials.gov/ct2/show/NCT03036150

Conclusions and key messages • SGLT2i:  intraglomerular hypertension – eGFR dip: occurs in CKD stages 3a, 3b, CKD –  eGFR slope, albuminuria, effects in large CV trials – CREDENCE study: stopped early due to efficacy – DAPA-CKD and empagliflozin studies • Effects relatively independent of HbA1c lowering CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; SGLT2i, sodium – glucose co-transporter 2 inhibitor; TGFB, tubuloglomerular feedback; UACR, urinary albumin:creatinine ratio

Ack Ackno nowled wledgm gmen ents ts • FSGS Study team (Toronto, Ottawa, • Grant funding: • Study participants Winnipeg) • UHN/MSH Research Team • Bruce Perkins • Heather N. Reich, Michelle Hladunewich, • Burns Laboratory, Ottawa Daniel Cattran, Syamantak Majumder 6 , • Daniel Drucker Bridgit B. Bowskill, M. Golam Kabir 6 , • Julie Lovshin Suzanne L. Advani, Ian W. Gibson M, • Vesta Lai, RN, CDE Manish M. Sood, Andrew Advani – Maria Maione, RN – Josephine Tse, RN • Colorado – Alana Lee, RN • Petter Bjornstad – Holly Tschirhart, RN • Salary support: • Students: • David Maahs – Yuliya Lytvyn, PhD – Marko Skrtic, MD PhD • Groningen – the Netherlands – Harindra Rajasekeran MSc • Hiddo Heerspink • EMPA-REG OUTCOME • Claire Dekkers – Bernard Zinman • Ron Gansevoort – Christoph Wanner – Silvio Inzucchi • Vancouver – DIAMOND trial – Gert Meyer – Subodh Verma • Sean Barbour