Diabetic Kidney Disease: Is it all diabetes? Rajiv Agarwal, MD - - PowerPoint PPT Presentation

Outcomes of SGLT2i in Diabetic Kidney Disease: Is it all diabetes?

Rajiv Agarwal, MD Indianapolis, IN, USA

June 14, 2019 - Budapest, Hungary

Outcomes of SGLT2i in diabetic kidney disease: is it all diabetes?

Rajiv Agarwal MD, MS Professor of Medicine Indiana University and VAMC, Indianapolis

Standard of Care to Prevent Progression

• f CKD

1. Wright JT Jr et al. JAMA. 2002;288(19):2421-2431. 2. Wright JT Jr et al. N Engl J Med. 2015;373(22):2103-2116. 3. Hebert LA et al. Hypertension. 1997;30(3 Pt 1):428-435. 4. Kidney Disease Improving Global Outcomes (KDIGO). KDIGO Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. https://kdigo.org/wp-content/uploads/2016/10/KDIGO-2012-Blood-Pressure-Guideline-English.pdf. Accessed May 7, 2019.

BP <130/80 mmHg1-3 RAAS inhibitors in patients with albumuinuria4

BP, blood pressure; RAAS, renin-angiotensin-aldosterone system.

3

Lewis Trial: Primary Outcome- DDT

Diabetes & Hypertension

ESRD

RENAAL: Irreversible Clinical Endpoints

12 24 36 48 Months 20 40 60 % Patients with an Event 762 715 610 348 43 43 43 43 43 43 751 714 625 375 68 68 68 68 68 68 Pbo Los

p=0.002 Risk Reduction: 28.6% (11.5, 42.4)

n at Risk Placebo Losartan

Outcome trials for CV safety in high-risk type 2 diabetes mellitus

All these trials designed to assure cardiovascular safety of the drugs i.e. non-inferiority trials Not designed to test or demonstrate renal efficacy

Outcome trials for CV safety in high-risk type 2 diabetes mellitus

SGLT-2 inhibitor trials

Empagliflozin EMPA-REG OUTCOME Canagliflozin CANVAS

SGLT-2 inhibitor trial designed to show renal protection

Canagliflozin CREDENCE

Outcome trials for CV safety in high-risk type 2 diabetes mellitus

SGLT-2 inhibitor trials

Empagliflozin EMPA-REG OUTCOME Canagliflozin CANVAS

SGLT-2 inhibitor trial designed to show renal protection

Canagliflozin CREDENCE

EMPA REG OUTCOME

Empagliflozin, 3 arms: 0, 10, 25 mg, n=7020 All with CVD, none with eGFR <30 Primary end-point: 3 point MACE

CV death Non-fatal MI Non-fatal stroke

Primary end-point: HR 0.86 (0.74-0.99)

Non-inferiority p <0.001 Superiority p=0.04

Zinman B et al, NEJM 2015

Outcome trials for CV safety in high-risk type 2 diabetes mellitus

SGLT-2 inhibitor trials

Empagliflozin EMPA-REG OUTCOME Canagliflozin CANVAS

SGLT-2 inhibitor trial designed to show renal protection

Canagliflozin CREDENCE

CANVAS

Canagliflozin, 3 arms: 0, 100, 300 mg, n=10142, 2 trials

Symptomatic ASCVD + age 30+ OR 2 CV risk factors + age 50+, exclude eGFR <30

Primary end-point: 3 point MACE

HR 0.86 (0.75-0.97) Non-inferiority p <0.001, Superiority p=0.02

Increased risk of leg amputation

HR 1.97, p<0.001

Neal B et al, NEJM 2017

Outcome trials for CV safety in high-risk type 2 diabetes mellitus

SGLT-2 inhibitor trials

Empagliflozin EMPA-REG OUTCOME Canagliflozin CANVAS

SGLT-2 inhibitor trial designed to show renal protection

Canagliflozin CREDENCE

CREDENCE

Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy Inclusion

albuminuria (UACR 300-5000 mg/g ) eGFR 30-90

Outcomes:

Primary outcome: time to first of end-stage kidney disease (ESKD), doubling of serum creatinine, renal or cardiovascular (CV) death. Secondary outcome:

CV composite: CV death, MI, stroke, hosp-CHF, hosp-USAP Individual components of renal composite: ESKD, doubling of serum creatinine, or renal death. All cause mortality

NCT02065791

Phase 3 CREDENCE Renal Outcomes Trial

• f Canagliflozin is Being Stopped Early for

Positive Efficacy Findings

RARITAN, N.J., July 16, 2018 – The Janssen Pharmaceutical Companies of Johnson & Johnson today announced that the Phase 3 CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) clinical trial, evaluating the efficacy and safety of canagliflozin versus placebo when used in addition to standard of care for patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), is being stopped early based on the achievement

• f pre-specified efficacy criteria.

The decision is based on a recommendation from the study’s Independent Data Monitoring Committee (IDMC) that met to review the data during a planned interim

• analysis. This recommendation was based on demonstration of efficacy, as the

trial had achieved pre-specified criteria for the primary composite endpoint of end- stage kidney disease (time to dialysis or kidney transplantation), doubling of serum creatinine, and renal or cardiovascular (CV) death, when used in addition to standard of care.

https://www.jnj.com/phase-3-credence-renal-outcomes-trial-of-invokana-canagliflozin-is-being-stopped-early-for-positive- efficacy-findings

EMPA-REG Secondary microvascular Progression to macro, 2x creat RRT, renal death + eGFR <45, 0.61 0.53-0.70 <0.001 Trial Definition HR p Post hoc 2x cr (+eGFR<45), RRT (n=27), renal death 0.54 0.40-0.75 <0.001 CANVAS: secondary Albuminuria progression 0.73 0.76-0.79 <0.05 Post hoc 40% eGFR (n=239), RRT (n=18), renal death (n=3) 0.60 0.47-0.77 <0.05

Renal outcomes SGLT-2 inhibitor trials

Low Renal Risk Populations in CV Outcomes Trials

Low Moderately increased High Very high

<30 30-44 45-59 60-90 ≥90

GFR categories (mL/min/1.73 m2) Albuminuria categories (mg/g)

A1: <30 A2: 30-300 A3: >300

D C E DECLARE CANVAS Program EMPA-REG OUTCOME Median UACR (mg/g) 13 12 18 Mean eGFR (mL/min/1.73 m2) 85 76 74

Total of 29 sustained RRT events reported across trials

Sustained RRT Events DECLARE Not reported CANVAS Program 18 EMPA-REG OUTCOME 11

D C E

Effects on Renal Outcomes in CREDENCE

Primary Outcome: ESKD, Doubling of Serum Creatinine, or Renal or CV Death

5 10 15 20 25 26 52 78 104 130 156 182

Participants with an event (%) Months since randomization

Hazard ratio, 0.70 (95% CI, 0.59–0.82) P = 0.00001

6 12 18 24 30 36 42

340 participants 245 participants Placebo Canagliflozin

• No. at risk

Placebo 2199 2178 2132 2047 1725 1129 621 170 Canagliflozin 2202 2181 2145 2081 1786 1211 646 196

Participants with an event (%)

ESKD, Doubling of Serum Creatinine, or Renal Death

5 10 15 20 25 26 52 78 104 130 156 182

Months since randomization

• No. at risk

Placebo 2199 2178 2131 2046 1724 1129 621 170 Canagliflozin 2202 2181 2144 2080 1786 1211 646 196

Hazard ratio, 0.66 (95% CI, 0.53–0.81) P <0.001 224 participants 153 participants

6 12 18 24 30 36 42

Participants with an event (%) Placebo Canagliflozin

End-stage Kidney Disease

5 10 15 20 25 26 52 78 104 130 156 182

Months since randomization

Hazard ratio, 0.68 (95% CI, 0.54–0.86) P = 0.002 165 participants 116 participants

6 12 18 24 30 36 42

Participants with an event (%)

• No. at risk

Placebo 2199 2182 2141 2063 1752 1152 641 178 Canagliflozin 2202 2182 2146 2091 1798 1217 654 199

Placebo Canagliflozin

Dialysis, Kidney Transplantation, or Renal Death*

5 10 15 20 25 26 52 78 104 130 156 182

Months since randomization

Hazard ratio, 0.72 (95% CI, 0.54–0.97) 105 participants 78 participants

• No. at risk

Placebo 2199 2183 2147 2077 1776 1178 653 180 Canagliflozin 2202 2184 2148 2100 1811 1236 661 199

6 12 18 24 30 36 42

Participants with an event (%) Placebo Canagliflozin

*Post hoc analysis.

Hazard ratio (95% CI) P value Primary composite outcome 0.70 (0.59–0.82) 0.00001 Doubling of serum creatinine 0.60 (0.48–0.76) <0.001 ESKD 0.68 (0.54–0.86) 0.002 eGFR <15 mL/min/1.73 m2 0.60 (0.45–0.80) – Dialysis initiated or kidney transplantation 0.74 (0.55–1.00) – Renal death 0.39 (0.08–2.03) – CV death 0.78 (0.61–1.00) 0.0502 ESKD, doubling of serum creatinine, or renal death 0.66 (0.53–0.81) <0.001 Dialysis, kidney transplantation, or renal death* 0.72 (0.54–0.97) –

Summary Forest Plot

Favors Canagliflozin Favors Placebo

0.25 0.5 1.0 2.0 4.0

*Post hoc analysis.

Effects on BP and glucose in CREDENCE

Effects on HbA1c

• 0,6
• 0,5
• 0,4
• 0,3
• 0,2
• 0,1

6 12 18 24 30 36 42

Months since randomization

Baseline (%) 8.3 8.3

Canagliflozin Placebo

ITT analysis

Mean difference over study –0.25% (95% CI: –0.31, –0.20)

• No. of participants

Placebo 2150 2103 2066 1981 1882 1728 1172 688 252 Canagliflozin 2154 2108 2074 2024 1909 1817 1254 729 274

–0.3 –0.4 –0.5 –0.6 –0.2 –0.1

LS mean change (±SE) in HbA1c (%)

Effects on Systolic BP

• 5
• 4
• 3
• 2
• 1

1 2 6 12 18 24 30 36 42

LS mean change (±SE) in systolic BP (mmHg) Months since randomization

• No. of participants

Placebo 2188 2131 2096 2027 1923 1766 1187 682 245 Canagliflozin 2190 2141 2096 2047 1962 1842 1261 731 264

Baseline (mmHg) 139.8 140.2

Canagliflozin Placebo Mean difference over study –3.30 mmHg (95% CI: –3.87, –2.73)

ITT analysis

– 1 – 2 – 3 – 4 – 5 1 2

Effects on Body Weight

• 3
• 2
• 1

1 6 12 18 24 30 36 42

LS mean change (±SE) in body weight (kg) Months since randomization

• No. of participants

Placebo 2187 2126 2092 2005 1917 1750 1179 679 244 Canagliflozin 2188 2134 2091 2023 1957 1830 1256 731 263

Baseline (kg)

87.3 86.9

Canagliflozin Placebo Mean difference over study –0.80 kg (95% CI: –0.92, –0.69)

ITT analysis

– 2 – 3 – 1 1

Summary

Na restriction, diet, smoking cessation, BP control, glycemic control, statins and RAAS inhibition are the current standards of care in DKD. SGLT-2 inhibitor protects the kidney in DKD. The effects on glycemic control, systolic BP, and body weight are relatively small. Thus, the benefit of SGLT-2 inhibition appears to be independent of diabetes and BP.

ADA has revised its guidelines

11.3 For patients with type 2 diabetes and diabetic kidney disease, consider use of an SGLT2 inhibitor in patients with an eGFR ≥ 30 mL/min/1.73m2 and particularly in those with > 300 mg/g albuminuria to reduce risk of CKD progression, cardiovascular events, or

• both. Grade of evidence: A