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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

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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

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SLIDE 2

2

Associate Professor Will Herrington @willkidney

CTSU, University of Oxford Honorary Consultant Nephrologist, Oxford Kidney Unit

The clinical landscape of managing patients with CKD: Where are we now and what can we expect?

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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

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EFFECT OF SGLT-2 INHIBITION ON: KIDNEY DISEASE PROGRESSION

S4

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Effect of Empagliflozin vs placebo on mean eGFR

66 68 70 72 74 76 78

Adjusted mean (SE) eGFR (mL/min/1.73m2) Week

Placebo Empagliflozin 10 mg Empagliflozin 25 mg

12 0 4 28 52 94 108 80 122 66 136 150 164 178 192 Wanner C et al. N Engl J Med 2016; 375:323-34

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Reversal of acute effect on eGFR

66 68 70 72 74 76 78

Adjusted mean (SE) eGFR (mL/min/1.73m2) Week

Placebo Empagliflozin 10 mg Empagliflozin 25 mg

12 0 4 28 52 94 108 80 122 66 136 150 164 178 192 Wanner C et al. N Engl J Med 2016; 375:323-34

4 weeks after stopping treatment

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S7

EMPA-REG OUTCOME: Kidney disease progression

Events/ participants Rate per 1000 pt years SGLT2i Placebo Hazard ratio (95% CI) SGLT2i better Placebo better

0.5 0.75 1 1.5 2 EMPA-REG OUTCOME† 152/7020 6.3 11.5 0.54 (0.40-0.75)

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

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First three large SGLT2i trials in type 2 diabetes: Kidney disease progression

Events/ participants Rate per 1000 pt years SGLT2i Placebo Hazard ratio (95% CI) SGLT2i better Placebo better

0.5 0.75 1 1.5 2 EMPA-REG OUTCOME† 152/7020 6.3 11.5 0.54 (0.40-0.75) CANVAS Program* 249/10142 5.5 9.0 0.60 (0.47-0.77) DECLARE-TIMI58* 365/17160 3.7 7.0 0.53 (0.43-0.66)

Outcomes † = Doubling of creatinine or ESRD * = 40% decline in eGFR or ESRD Wanner NEJM 2016: 375: 323-334; Neal NEJM 2017; 377: 644- 57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14.

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All four large SGLT2i trials in type 2 diabetes: Kidney disease progression

Between trial heterogeneity p=0.50 Events/ participants Rate per 1000 pt years SGLT2i Placebo Hazard ratio (95% CI) SGLT2i better Placebo better

0.5 0.75 1 1.5 2 EMPA-REG OUTCOME† 152/7020 6.3 11.5 0.54 (0.40-0.75) CANVAS Program* 249/10142 5.5 9.0 0.60 (0.47-0.77) DECLARE-TIMI58* 365/17160 3.7 7.0 0.53 (0.43-0.66) CREDENCE† 377/4401 27.0 40.4 0.66 (0.53-0.81)

All 4 trials

0.59 (0.52-0.66)

Outcomes † = Doubling of creatinine or ESRD * = 40% decline in eGFR or ESRD Wanner NEJM 2016: 375: 323-334; Neal NEJM 2017; 377: 644- 57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14.

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Four large SGLT2i trials in type 2 diabetes: Acute Kidney Injury (AKI)

Heterogeneity between trials p = 0.68

Events/ participants Rate per 1000 pt years SGLT2i Placebo Hazard ratio (95% CI) SGLT2i better Placebo better

0.5 0.75 1 1.5 2 EMPA-REG OUTCOME 401/7020 16.9 21.4 0.76 (0.62-0.93) CANVAS Program 58/10142 1.6 2.5 0.66 (0.39-1.11) DECLARE-TIMI58 300/17160 3.6 5.0 0.69 (0.55-0.87) CREDENCE 184/4397 16.9 20.0 0.85 (0.64-1.13)

All 4 trials

0.75 (0.66-0.85)

Wanner NEJM 2016: 375: 323-334; Neal NEJM 2017; 377: 644- 57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14.

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EFFECT OF SGLT-2 INHIBITION ON: CARDIOVASCULAR RISK

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Four large SGLT2i trials in type 2 diabetes: MACE (primary) outcome

Heterogeneity between trials p = 0.48 0.5 0.75 1 1.5 2 EMPA-REG OUTCOME 772/7020 37.4 43.9 0.86 (0.74-0.99) CANVAS Program 1011/10142 26.9 31.5 0.86 (0.75-0.97) DECLARE-TIMI58 1559/17160 22.6 24.2 0.93 (0.84-1.03) CREDENCE* 486/4401 38.7 48.7 0.80 (0.67-0.95)

All 4 trials

0.88 (0.82-0.94) Events/ participants Rate per 1000 pt years SGLT2i Placebo Hazard ratio (95% CI) SGLT2i better Placebo better

Zinman NEJM 2015: 373: 2117-28; Neal NEJM 2017; 377: 644-57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14.

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Between trial heterogeneity p=0.72

Four large SGLT2i trials in type 2 diabetes: Heart failure hospitalization

Events/ participants Rate per 1000 pt years SGLT2i Placebo Hazard ratio (95% CI) SGLT2i better Placebo better

0.5 0.75 1 1.5 2 EMPA-REG OUTCOME 221/7020 9.4 14.5 0.65 (0.50-0.85) CANVAS Program 243/10142 5.5 8.7 0.67 (0.52-0.87) DECLARE-TIMI58 498/17160 6.2 8.5 0.73 (0.61-0.88) CREDENCE 230/4401 15.7 25.3 0.61 (0.47-0.80)

All 4 trials

0.68 (0.60-0.76)

Zinman NEJM 2015: 373: 2117-28; Neal NEJM 2017; 377: 644-57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14.

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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

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

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?

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

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  • Yes. More data = important

SGLT-2i has side effects, and prescribers need evidence of benefit from currently understudied populations

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Effects of Empagliflozin vs placebo on %HbA1c, by eGFR

17 Cherney et al. Kidney International 2018; 93: 231-244 17

  • 1.0%
  • 0.5%

+0.5% Number of measurements Empagliflozin Placebo %HbA1c difference (95% CI) p value for interaction

%HbA1c

eGFR (mL/min/1.73m2) ≥90 348 343

  • 0.84 (-0.95, -0.72)

<0.001 ≥60 to <90 518 516

  • 0.60 (-0.70, -0.51)

≥30 to <60 234 239

  • 0.38 (-0.52, -0.24)

<30 42 46

  • 0.04 (-0.37, 0.29)
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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/1,73m2 (200 events)

– Excluded people with type 1 DM, or prior ketoacidosis, or a recent history of lower limb amputation/ischaemia or foot infections

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EFFECT OF SGLT-2 INHIBITION ON: SAFETY OUTCOMES

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Four large SGLT2i trials in type 2 diabetes: Amputation

Between trial heterogeneity p=0.02 Events/ participants Rate per 1000 pt years SGLT2i Placebo Hazard ratio (95% CI) SGLT2i better Placebo better

0.5 0.75 1 1.5 2 EMPA-REG OUTCOME 131/7020 6.5 6.5 1.01 (0.70-1.44) CANVAS program 187/10142 6.3 3.4 1.97 (1.41-2.75) DECLARE-TIMI58 236/17160 3.6 3.3 1.09 (0.84-1.40) CREDENCE 133/4397 12.3 11.2 1.11 (0.79-1.56)

All 4 trials

1.23 (1.05-1.44)

Zinman NEJM 2015: 373: 2117-28; Neal NEJM 2017; 377: 644-57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14.

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Four large SGLT2i trials in type 2 diabetes: Mycotic genital infections

Heterogeneity between trials p = 0.07 †Not collected in CANVAS-R

SGLT2i better Placebo better Events/ participants Rate per 1000 pt years SGLT2i Placebo Hazard ratio (95% CI)

1 1.5 2 4 8 EMPA-REG OUTCOME 343/7020 26.0 7.3 3.55 (2.57-4.91) CANVAS Program (Female) 196/4330 69.0 18.0 4.37 (2.78-6.88) CANVAS Program (Male) 503/10142 35.0 11.0 3.76 (2.91-4.86) DECLARE-TIMI58 85/17160 2.2 0.3 8.36 (4.19-16.68) CREDENCE (Female) 32/1492 12.6 6.1 2.10 (1.00-4.45) CREDENCE (Male) 31/2905 8.4 0.9 9.30 (2.83-30.60)

All 4 trials

3.92 (3.31-4.65)

Zinman NEJM 2015: 373: 2117-28; Neal NEJM 2017; 377: 644-57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14.

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Fournier’s gangrene

  • FDA warning: result of 12 cases reported over 5y

during which time est. 1.7M users of SGLT-2 inhibitors

S22 https://www.fda.gov/Drugs/DrugSafety/ucm617360.htm

Cases Trial(s) Number of participants SGLT2i (n=21266) Placebo (n=17457) EMPA-REG OUTCOME 7,020 CANVAS/CREDENCE 10,142+4,401 2 2 DECLARE-TIMI58 17,160 1 5 Total 3 7

Wiviott NEJM 2018; Nov 10; Perkovic Tweet (16May19:1652); Herrington, CKJ 2018: 749-761 (open access)

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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

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Herrington, CKJ 2018: 749-761 (open access)

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Ongoing large placebo-controlled SGLT-2i trials in: CKD (with or without diabetes)

Trial Key eligibility Size Primary outcome: ESKD, or death from renal or CV causes + End Dapa-CKD (Dapagliflozin) CKD

  • eGFR 25-75, AND

uACR 200-5000 ~4000 Sustained ≥50% decline in eGFR Nov 2020 EMPA- KIDNEY (Empagliflozin) CKD

  • eGFR 20-45, OR
  • eGFR 45-90+uACR ≥200

~5000 Sustained ≥40% decline in eGFR June 2022

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Ongoing large placebo-controlled SGLT-2i trials: Type 2 diabetes or heart failure populations

Heart failure (Diabetes & non-diabetes)

EMPORER-Reduced (Empagliflozin) EMPORER-Preserved (Empagliflozin) Dapa-HF (Dapagliflozin) DELIVER (Dapagliflozin)

Type 2 diabetes VERTIS CV (Ertugliflozin) SCORED* (Sotagliflozin) SOLOIST-WHF (Sotagliflozin)

* Restricted to eGFR 25-60

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Conclusions (1)

  • SGLT2 inhibition + RAS blockade likely to be a new

standard of care among certain people with type 2 diabetes and proteinuric diabetic kidney disease

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Conclusions (2)

  • SGLT2 inhibition + RAS blockade likely to be a new standard of

care among certain people with type 2 diabetes and proteinuric diabetic kidney disease

– Priority FDA regulatory review of CREDENCE awaited

  • More randomized data = important
  • Understudied populations include those with:

– Non-diabetic causes of kidney disease (regardless of eGFR/uACR/DM) – Low levels of kidney function (e.g. eGFR <30) typical of renal clinics – Diabetic kidney disease with eGFR<45 + uACR <300 mg/g

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EXTRA SLIDES

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Ongoing large placebo-controlled SGLT-2i trials in: Type 2 DM populations

Trial Key eligibility Size Primary outcome(s) End VERTIS CV (Ertugliflozin) Prior CV disease 17,276

  • MACE

Dec 2019 SCORED (Sotagliflozin) eGFR 25-60 ~10,600

  • MACE
  • CV death + Hosp. for HF

Mar 2022 SOLOIST-WHF (Sotagliflozin) Worsening HF ~4000

  • CV death + Hosp. for HF

June 2021

All 3 trials have planned kidney progression outcomes as secondary analyses

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Ongoing large placebo-controlled SGLT-2i trials in: Heart Failure (HF) populations (with and without DM)

Trial Key eligibility Size Primary outcome End EMPORER- Reduced (Empagliflozin) Class II–IV HF (LVEF ≤40%) ~2850

  • CV death + Hosp. for HF*

Jun 2020 EMPORER- Preserved (Empagliflozin) Symptomatic HF (LVEF>40% + NT-proBNP>300) ~6000

  • CV death + Hosp. for HF*

Oct 2020 Dapa-HF (Dapagliflozin) Symptomatic HF (LVEF ≤40% + NT-proBNP >600) 4,744

  • CV death + Hosp. for HF*

Jul 2019 DELIVER (Dapagliflozin) Symptomatic HF (LVEF>40% + NT-proBNP ↑) ~4,700

  • CV death + Hosp. for HF

Jun 2021

* Kidney progression +/- eGFR slope based secondary outcomes also planned

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Zelniker Lancet 2018, Nov 10

Between trial heterogeneity p=0.02

Four large SGLT2 inhibitor trials in type 2 diabetes: CV death

Events/ participants Rate per 1000 pt years SGLT2i Placebo Hazard ratio (95% CI) SGLT2i better Placebo better

0.5 0.75 1 1.5 2 EMPA-REG OUTCOME 309/7020 12.4 20.2 0.62 (0.49-0.77) CANVAS Program 453/10142 11.6 12.8 0.87 (0.72-1.06) DECLARE-TIMI58 494/17160 7.0 7.1 0.98 (0.82-1.17) CREDENCE 250/4401 19.0 24.4 0.78 (0.61-1.00)

All 4 trials

0.83 (0.75-0.92)

Zinman NEJM 2015: 373: 2117-28; Neal NEJM 2017; 377: 644-57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14.

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0.4 0.6 0.8 1 1.5

Empagliflozin (n=4687) Placebo (n=2333) Hazard ratio (95% CI) p value for interaction

Empagliflozin better Placebo better Cardiovascular death or hospitalization for heart failure

eGFR (mL/min/1.73m2) ≥90 36/1050 (3.4%) 25/488 (5.1%)

0.85

≥60 to <90 117/2423 (4.8%) 96/1238 (7.8%) ≥45 to <60 71/831 (8.5%) 48/418 (11.5%) <45 41/381 (10.8%) 29/189 (15.3%)

All participants 265 (5.7%)

198 (8.5%)

0.66 (0.55-0.79)

Effect of Empagliflozin vs placebo on: CV DEATH or HEART FAILURE

EMPA-KIDNEY rational paper in Clinical Kidney Journal (open access):

https://academic.oup.com/ckj/article/11/6/749/5144684

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0.2 0.4 0.60.81 1.5

Empagliflozin (n=4687) Placebo (n=2333) Hazard ratio (95% CI) P value for interaction

Empagliflozin better Placebo better

Urinary albumin:creatinine ratio (uACR, mg/g)

<30 22/2766 (0.8%) 26/1376 (1.9%)

0.51

≥30 to ≤300 23/1325 (1.7%) 17/671 (2.5%) >300 33/504 (6.5%) 28/260 (10.8%)

All participants 81 (1.7%) 71 (3.1%) 0.54 (0.40-0.75)

52 participants with missing baseline or post-baseline creatinine data (with no evidence of RRT or renal death) were excluded.

Effect of Empagliflozin vs placebo on: Kidney disease progression, by uACR

Herrington, CKJ 2018: 749-761 (open access)

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CREDENCE Kidney disease progression, by eGFR & uACR

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Interaction test

Perkovic NEJM 2019; Apr 14.

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Albuminuria predicts ESKD, irrespective of primary renal diagnosis

Cystic kidney disease Glomerulo- nephritis Diabetic nephropathy Other recorded diagnoses

Urinary albumin:creatinine ratio (mg/g)* <30 (normo-) 1.00 1.00 1.00 1.00 30 to 300 (micro-) 1.18 (0.88, 1.58) 2.39 (1.03, 5.54) 1.64 (0.79, 3.41) 1.39 (1.05, 1.84) >300 (macro-) 1.21 (0.87, 1.69) 7.26 (3.22, 16.36) 5.85 (2.98, 11.49) 3.91 (2.99, 5.10)

*Interactions between albuminuria group and diagnoses of cystic kidney disease, glomerulonephritis and diabetic nephropathy, after adjustment for age, sex, country, race, treatment allocation, prior diseases and medication, lipids, smoking, blood pressure, BMI, phosphate, haemoglobin and eGFR.

Haynes R. et al. AJKD 2014; 64(1):40-8

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SGLT-2 inhibition in people without diabetes

  • 376 participants without DM
  • Canagliflozin (various doses) vs placebo
  • Reductions in:

– Body weight (by ~1.5%) – eGFR (by ~1 mL/min/1.73m2)

  • Characteristic changes in Hct and urate
  • Mycotic genital infections increases
  • Well tolerated with no risk of hypoglycaemia

S36 Bays Obesity (2014) 22, 1042-1049.

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Effects of Empagliflozin vs placebo on WEIGHT, by eGFR

37 Cherney et al. Kidney International 2018; 93: 231-244

  • 3
  • 2
  • 1

1 Number of measurements Empagliflozin Placebo Weight difference (95% CI) p value for interaction

Weight, Kg

eGFR (mL/min/1.73m2) ≥90 348 343

  • 1.9 (-2.3, -1.5)

0.09 ≥60 to <90 518 516

  • 2.0 (-2.3, -1.7)

≥30 to <60 234 239

  • 1.4 (-1.8, -0.9)

<30 42 46

  • 1.5 (-2.5, -0.4)
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Effects of Empagliflozin vs placebo on SYSTOLIC BP, by eGFR

38 Cherney et al. Kidney International 2018; 93: 231-244

  • 12 -10 -8
  • 6
  • 4
  • 2

2 Number of measurements Empagliflozin Placebo SBP difference (95% CI) p value for interaction

SBP, mmHg

eGFR (mL/min/1.73m2) ≥90 348 343

  • 3.2 (-4.9, -1.5)

0.26 ≥60 to <90 518 516

  • 4.0 (-5.4, -2.6)

≥30 to <60 234 239

  • 5.5 (-7.6, -3.4)

<30 42 46

  • 6.6 (-11.4, -1.8)
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EASE: Ketoacidosis in type 1 diabetes

  • EASE-2/-3 trials 26 weeks trial in type 1 DM
  • Reduced HbA1c by 0.5%
  • Reduced weight by ~3Kg
  • DKA risk is particularly high among women & those on an

insulin pump

S39 Rosenstock Diabetes Care 2018 41(12): 2560-2569

Placebo n=484 10mg n=491 25mg n=489 Confirmed ketoacidosis 6 (1.2%) 21 (4.3%) 16 (3.3%)

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S40

Four large SGLT2i trials in type 2 diabetes: Ketoacidosis

Between trial heterogeneity p=0.54 Events/ participants Rate per 1000 pt years SGLT2i Placebo Hazard ratio (95% CI) SGLT2i better Placebo better

0.5 0.75 1 1.5 2 4 EMPA-REG OUTCOME 5/7020 0.1 <0.1 1.99 (0.22-17.80) CANVAS Program 18/10142 0.6 0.3 2.33 (0.76-7.17) DECLARE-TIMI58 39/17160 0.9 0.4 2.18 (1.10-4.30) CREDENCE 12/4397 2.2 0.2 10.80 (1.39-83.65)

All 4 trials

2.46 (1.43-4.24)

Zinman NEJM 2015: 373: 2117-28; Neal NEJM 2017; 377: 644-57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14.

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S41

Four large SGLT2 inhibitor trials in type 2 diabetes: Urinary tract infections

Heterogeneity between trials p = 0.54 †Not collected in CANVAS-R

Events/ participants Rate per 1000 pt years SGLT2i Placebo Hazard ratio (95% CI) SGLT2i better Placebo better

0.5 0.75 1 1.5 2 EMPA-REG OUTCOME 1265/7020 82.0 79.0 0.96 (0.85-1.08) CANVAS Program 440/4330 40.0 37.0 1.09 (0.89-1.34) DECLARE-TIMI58 260/17160 3.6 3.8 0.93 (0.73-1.18) CREDENCE 466/4397 48.3 45.1 1.08 (0.90-1.29)

All 4 trials

1.00 (0.92-1.09)

Zinman NEJM 2015: 373: 2117-28; Neal NEJM 2017; 377: 644-57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14.

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S42

4 large trials in type 2 diabetes: Fractures

Between trial heterogeneity p= 0.29 Events/ participants Rate per 1000 pt years SGLT2i Placebo Hazard ratio (95% CI) SGLT2i better Placebo better

0.5 0.75 1 1.5 2 EMPA-REG OUTCOME 270/7020 15.2 16.1 0.98 (0.76-1.25) CANVAS Program NA/10142 15.4 11.9 1.26 (1.04-1.52) DECLARE-TIMI58 897/17160 13.6 13.2 1.04 (0.91-1.18) CREDENCE 135/4397 11.8 12.1 0.98 (0.70-1.37)

All 4 trials

1.08 (0.98-1.18)

Zinman NEJM 2015: 373: 2117-28; Neal NEJM 2017; 377: 644-57; Wiviott NEJM 2018; Nov 10; Perkovic NEJM 2019; Apr 14.

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0.2 0.4 1 2 4 8

Effect of Empagliflozin vs placebo on: Hyperkalaemia

Empagliflozin (n=4687) Placebo (n=2333) Hazard ratio (95% CI) p value for interaction

Empagliflozin better Placebo better

Hyperkalaemia

≥60 46/3473 (1.3%) 36/1726 (2.1%) ≥45 to <60 33/831 (4.0%) 29/418 (6.9%) <45 14/381 (3.7%) 13/189 (6.9%)

0.72

All participants93 (2.0%)

78 (3.3%)

0.57 (0.42-0.77)

eGFR (mL/min/1.73m2)

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CREDENCE: Renal “safety”

Number of participants with an event, n Canagliflozin (N = 2200) Placebo (N = 2197) Hazard ratio (95% CI) All renal-related AEs 290 388 0.71 (0.61–0.82) Hyperkalemia 151 181 0.80 (0.65–1.00) Acute kidney injury 86 98 0.85 (0.64–1.13) Favors Canagliflozin Favors Placebo

0.5 1.0 2.0

Includes all treated participants through 30 days after last dose.

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SLIDE 45

S45

Zelniker Lancet 2018, Nov 10

standard het test p=0.07)

3 large trials in type 2 diabetes: Primary MACE outcome, by prior CVD

0.5 0.75 1 1.5 2 Prior CV disease 2588/20650 0.86 (0.80-0.93) No prior CV disease 754/13672 1.00 (0.87-1.16)

All participants in all 3 trials

0.89 (0.83-0.96)

Events/ participants

Hazard ratio (95% CI) SGLT2i better Placebo better

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S46

Zelniker Lancet 2018, Nov 10

Standard Het test p=0.08

3 large trials in type 2 diabetes: CV death, by prior CV disease

0.5 0.75 1 1.5 2 Prior CV disease 987/20650 0.80 (0.71-0.91) No prior CV disease 269/13672 1.02 (0.80-1.30)

All participants in all 3 trials

0.84 (0.75-0.94)

Events/ participants

Hazard ratio (95% CI) SGLT2i better Placebo better

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SLIDE 47

S47

CANVAS

  • 10,142 participants with type 2 DM
  • Placebo-controlled & double-blind
  • Active: Canagliflozin 100/300 mg
  • Follow-up: 2.4 years
  • Prior atherosclerotic CV disease: 66%
  • eGFR <60 mL/min/1.73m2: 20%

Primary composite outcome

  • CV death, MI or stroke:

↓14% (HR 0.86, 95%CI 0.75-0.97)

Neal NEJM 2017; 377: 644-57

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SLIDE 48

S48

DECLARE

  • 17,160 participants with type 2 DM
  • Placebo-controlled & double-blind
  • Active: Dapagliflozin 10 mg
  • Follow-up: 4.2 years
  • Prior atherosclerotic CV disease: 41%
  • eGFR <60 mL/min/1.73m2: 7%

Primary composite outcomes

  • CV death, MI or stroke:

NS (HR 0.93, 95%CI 0.84-1.03)

  • CV death or Heart failure hosp.:

↓17% (HR 0.83, 95%CI 0.73-0.95)

Wiviott NEJM 2018; Nov 10

slide-49
SLIDE 49

Effect of Empagliflozin vs placebo on: ACUTE KIDNEY INJURY (AKI) in first 30 days

Placebo Empagliflozin 10mg Empagliflozin 25mg (n=2333) (n=2345) (n=2342) Acute kidney injury report* 16 (0.7%) 20 (0.9%) 21 (0.9%)

* Any MedDRA Preferred Term which relates to acute renal failure