managing patients with CKD: Where are we now and what can we - PowerPoint PPT Presentation

The clinical landscape of managing patients with CKD: Where are we now and what can we expect? Will Herrington, MD Oxford, UK June 14, 2019 - Budapest, Hungary

The clinical landscape of managing patients with CKD: Where are we now and what can we expect? Associate Professor Will Herrington @willkidney CTSU, University of Oxford Honorary Consultant Nephrologist, Oxford Kidney Unit 2

Objectives • Summarize the key randomized data from the completed large placebo-controlled SGLT-2 inhibitor (SGLT2i) trials • Introduce the ongoing SGLT2i trials in diabetes, renal and heart failure populations S3

EFFECT OF SGLT-2 INHIBITION ON: KIDNEY DISEASE PROGRESSION S4

Effect of Empagliflozin vs placebo on mean eGFR 78 Placebo Empagliflozin 10 mg Empagliflozin 25 mg Adjusted mean (SE) eGFR 76 (mL/min/1.73m 2 ) 74 72 70 68 66 0 4 12 28 52 66 80 94 108 122 136 150 164 178 192 Week Wanner C et al. N Engl J Med 2016; 375:323-34

Reversal of acute effect on eGFR 4 weeks after stopping treatment 78 Placebo Empagliflozin 10 mg Empagliflozin 25 mg Adjusted mean (SE) eGFR 76 (mL/min/1.73m 2 ) 74 72 70 68 66 0 4 12 28 52 66 80 94 108 122 136 150 164 178 192 Week Wanner C et al. N Engl J Med 2016; 375:323-34

EMPA-REG OUTCOME: Kidney disease progression Rate per 1000 pt years Events/ SGLT2i Placebo Hazard ratio (95% CI) participants EMPA-REG OUTCOME † 0.54 (0.40-0.75) 152/7020 6.3 11.5 0.5 0.75 1 1.5 2 SGLT2i better Placebo better Wanner NEJM 2016: 375: 323-334; Neal NEJM 2017; 377: 644- 57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14. Outcomes † = Doubling of creatinine or ESRD S7

First three large SGLT2i trials in type 2 diabetes: Kidney disease progression Rate per 1000 pt years Events/ SGLT2i Placebo Hazard ratio (95% CI) participants EMPA-REG OUTCOME † 0.54 (0.40-0.75) 152/7020 6.3 11.5 CANVAS Program* 0.60 (0.47-0.77) 249/10142 5.5 9.0 0.53 (0.43-0.66) DECLARE-TIMI58* 3.7 7.0 365/17160 0.5 0.75 1 1.5 2 SGLT2i better Placebo better Wanner NEJM 2016: 375: 323-334; Neal NEJM 2017; 377: 644- 57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14. Outcomes † = Doubling of creatinine or ESRD S8 * = 40% decline in eGFR or ESRD

All four large SGLT2i trials in type 2 diabetes: Kidney disease progression Rate per 1000 pt years Events/ SGLT2i Placebo Hazard ratio (95% CI) participants EMPA-REG OUTCOME † 0.54 (0.40-0.75) 152/7020 6.3 11.5 CANVAS Program* 0.60 (0.47-0.77) 249/10142 5.5 9.0 0.53 (0.43-0.66) DECLARE-TIMI58* 3.7 7.0 365/17160 CREDENCE † 0.66 (0.53-0.81) 377/4401 27.0 40.4 0.59 (0.52-0.66) All 4 trials 0.5 0.75 1 1.5 2 SGLT2i better Placebo better Between trial heterogeneity p=0.50 Wanner NEJM 2016: 375: 323-334; Neal NEJM 2017; 377: 644- 57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14. Outcomes † = Doubling of creatinine or ESRD S9 * = 40% decline in eGFR or ESRD

Four large SGLT2i trials in type 2 diabetes: Acute Kidney Injury (AKI) Rate per 1000 pt years Events/ SGLT2i Placebo Hazard ratio (95% CI) participants 0.76 (0.62-0.93) EMPA-REG OUTCOME 401/7020 16.9 21.4 CANVAS Program 0.66 (0.39-1.11) 58/10142 1.6 2.5 0.69 (0.55-0.87) DECLARE-TIMI58 300/17160 3.6 5.0 0.85 (0.64-1.13) CREDENCE 184/4397 16.9 20.0 0.75 (0.66-0.85) All 4 trials 0.5 0.75 1 1.5 2 SGLT2i better Placebo better Heterogeneity between trials p = 0.68 Wanner NEJM 2016: 375: 323-334; Neal NEJM 2017; 377: 644- 57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14. S10

EFFECT OF SGLT-2 INHIBITION ON: CARDIOVASCULAR RISK S11

Four large SGLT2i trials in type 2 diabetes: MACE (primary) outcome Rate per 1000 pt years Events/ participants SGLT2i Placebo Hazard ratio (95% CI) 0.86 (0.74-0.99) EMPA-REG OUTCOME 772/7020 37.4 43.9 CANVAS Program 0.86 (0.75-0.97) 26.9 31.5 1011/10142 0.93 (0.84-1.03) DECLARE-TIMI58 1559/17160 22.6 24.2 0.80 (0.67-0.95) CREDENCE* 486/4401 38.7 48.7 0.88 (0.82-0.94) All 4 trials 0.5 0.75 1 1.5 2 SGLT2i better Placebo better Heterogeneity between trials p = 0.48 Zinman NEJM 2015: 373: 2117-28; Neal NEJM 2017; 377: 644-57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14. S12

Four large SGLT2i trials in type 2 diabetes: Heart failure hospitalization Rate per 1000 pt years Events/ SGLT2i Placebo Hazard ratio (95% CI) participants 0.65 (0.50-0.85) EMPA-REG OUTCOME 221/7020 9.4 14.5 CANVAS Program 0.67 (0.52-0.87) 243/10142 5.5 8.7 0.73 (0.61-0.88) DECLARE-TIMI58 498/17160 6.2 8.5 0.61 (0.47-0.80) 15.7 25.3 CREDENCE 230/4401 0.68 (0.60-0.76) All 4 trials 0.5 0.75 1 1.5 2 SGLT2i better Placebo better Between trial heterogeneity p=0.72 Zinman NEJM 2015: 373: 2117-28; Neal NEJM 2017; 377: 644-57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14. S13

CREDENCE • Overwhelming evidence of net benefit in the studied population • Absolute effects on outcomes (4401 participants + 2.6y follow-up) – Cardiovascular death 30 fewer – Dialysis/transplant/renal death 27 fewer – Ketoacidosis 10 extra S14

Should we continue to trial SGLT2 inhibition in people with type 2 diabetes? ? S15

Should we continue to trial SGLT2 inhibition in people with type 2 diabetes? Yes. More data = important SGLT-2i has side effects, and prescribers need evidence of benefit from currently understudied populations S16

Effects of Empagliflozin vs placebo on %HbA1c, by eGFR %HbA1c difference p value for Number of measurements (95% CI) interaction Empagliflozin Placebo eGFR (mL/min/1.73m 2 ) ≥ 90 -0.84 (-0.95, -0.72) 348 343 ≥ 60 to <90 -0.60 (-0.70, -0.51) 518 516 <0.001 ≥ 30 to <60 -0.38 (-0.52, -0.24) 234 239 -0.04 (-0.37, 0.29) <30 42 46 -1.0% -0.5% 0 +0.5% %HbA1c 17 17 Cherney et al. Kidney International 2018; 93: 231-244

CREDENCE • Overwhelming evidence of net benefit in the studied population • Absolute effects on outcomes – Cardiovascular death 30 fewer – Dialysis/transplant/renal death 27 fewer – Ketoacidosis 10 extra • Restricted to proteinuric diabetic kidney disease in type 2 DM – Mean eGFR 56 (SD 18) & uACR 929 mg/g – Limited evidence on kidney progression among those with: • uACR ≤1000 mg/g (60 events) or eGFR <45 mL/min/1,73m 2 (200 events) – Excluded people with type 1 DM, or prior ketoacidosis, or a recent history of lower limb amputation/ischaemia or foot infections S18

EFFECT OF SGLT-2 INHIBITION ON: SAFETY OUTCOMES S19

Four large SGLT2i trials in type 2 diabetes: Amputation Rate per 1000 pt years Events/ SGLT2i Placebo Hazard ratio (95% CI) participants 1.01 (0.70-1.44) 6.5 6.5 EMPA-REG OUTCOME 131/7020 CANVAS program 1.97 (1.41-2.75) 6.3 3.4 187/10142 1.09 (0.84-1.40) 3.6 3.3 DECLARE-TIMI58 236/17160 1.11 (0.79-1.56) CREDENCE 133/4397 12.3 11.2 1.23 (1.05-1.44) All 4 trials 0.5 0.75 1 1.5 2 SGLT2i better Placebo better Between trial heterogeneity p=0.02 Zinman NEJM 2015: 373: 2117-28; Neal NEJM 2017; 377: 644-57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14. S20

Four large SGLT2i trials in type 2 diabetes: Mycotic genital infections Rate per 1000 pt years Events/ SGLT2i Placebo Hazard ratio (95% CI) participants 3.55 (2.57-4.91) EMPA-REG OUTCOME 343/7020 26.0 7.3 CANVAS Program (Female) 196/4330 4.37 (2.78-6.88) 69.0 18.0 CANVAS Program (Male) 3.76 (2.91-4.86) 503/10142 35.0 11.0 8.36 (4.19-16.68) DECLARE-TIMI58 85/17160 2.2 0.3 CREDENCE (Female) 2.10 (1.00-4.45) 12.6 6.1 32/1492 9.30 (2.83-30.60) CREDENCE (Male) 31/2905 8.4 0.9 3.92 (3.31-4.65) All 4 trials 1 1.5 2 4 8 SGLT2i better Placebo better Heterogeneity between trials p = 0.07 †Not collected in CANVAS -R Zinman NEJM 2015: 373: 2117-28; Neal NEJM 2017; 377: 644-57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14. S21

Fournier’s gangrene • FDA warning: result of 12 cases reported over 5y during which time est. 1.7M users of SGLT-2 inhibitors Cases Trial(s) Number of SGLT2i Placebo participants (n=21266) (n=17457) EMPA-REG OUTCOME 7,020 0 0 CANVAS/CREDENCE 10,142+4,401 2 2 DECLARE-TIMI58 17,160 1 5 Total 3 7 https://www.fda.gov/Drugs/DrugSafety/ucm617360.htm Wiviott NEJM 2018; Nov 10; Perkovic Tweet (16May19:1652); Herrington, CKJ 2018: 749-761 (open access) S22

Types of patient from renal clinics not yet represented in the completed large SGLT-2i trials – Diabetic kidney disease with low levels of albuminuria (uACR <300 mg/g) – Non-diabetic causes of kidney disease (regardless of eGFR/uACR/DM) – Low levels of kidney function (e.g. eGFR <30) typical of renal clinics – Type 1 diabetes mellitus Herrington, CKJ 2018: 749-761 (open access) S23

Ongoing large placebo-controlled SGLT-2i trials in: CKD (with or without diabetes) Size Primary outcome: End Trial Key eligibility ESKD, or death from renal or CV causes + CKD Sustained ≥50% Dapa-CKD Nov - eGFR 25-75, AND ~4000 (Dapagliflozin) decline in eGFR 2020 uACR 200-5000 EMPA- CKD Sustained ≥40% June KIDNEY - eGFR 20-45, OR ~5000 decline in eGFR 2022 - eGFR 45- 90+uACR ≥200 (Empagliflozin)