Canagliflozin and Renal Outcomes

in Type 2 Diabetes and Nephropathy

CREDENCE trial

V. Perkovic, M.J. Jardine, B. Neal, S. Bompoint, H.J.L. Heerspink, D.M. Charytan,

R. Edwards, R. Agarwal, G. Bakris, S. Bull, C.P. Cannon, G. Capuano, P.-L. Chu,
D. de Zeeuw, T. Greene, A. Levin, C. Pollock, D.C. Wheeler, Y. Yavin, H. Zhang,
B. Zinman, G. Meininger, B.M. Brenner, and K.W. Mahaffey,
for the CREDENCE Trial Investigators*

NEJM April 2019

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The roadmap..

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 Objective

 To assess the effects of the SGLT2 inhibitor canagliflozin on renal

outcomes in patients with type 2 diabetes & albuminuric CKD

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 Study design

 Multicenter

 Randomized

 Double blind

 Placebo controlled trial

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 Inclusion Criteria
1. Age ≥30 years

2. History of type 2 diabetes mellitus

3. HbA1c 6.5% -12.0%

4. eGFR 30-90 mL/minute/1.73m2

5. Macroalbuminuria (UACR >300 to 5000 mg/g)

6. Treatment with stable dose of ACEi or ARB for at least 4 weeks prior to screening

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 Exclusion Criteria

1. Suspected Non diabetic kidney disease

2. Type 1 diabetes

3. Treated with immunosuppression for kidney disease

4. History of dialysis or kidney transplantation

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 Primary outcomes

Composite of

 ESKD (dialysis for at least 30 days, kidney transplantation, or an

eGFR of <15 ml/min/1.73 m2 sustained for at least 30 days)

 Doubling of serum creatinine level from baseline sustained for at

least 30 days

 Death from renal or cardiovascular disease

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 Secondary outcomes

1. A composite of cardiovascular death or hospitalization for heart failure

2. A composite of cardiovascular death, MI, or stroke

3. Hospitalization for heart failure

4. A composite of ESKD, doubling of the serum creatinine level, or renal death

5. Cardiovascular death

6. Death from any cause

7. A composite of cardiovascular death, MI, stroke, or hospitalization for heart failure or for
unstable angina

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Key Baseline Characteristics
Primary composite outcome Hazard Ratio, 0.70

(95% CI, 0.59–0.82)

RRR = 30%

NNT = 22

P=0.00001
Hazard Ratio, 0.66 (95% CI, 0.53–0.81)

RRR = 34%

NNT = 28

P<0.001

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Secondary outcomes

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Secondary outcomes

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Subgroup analysis according to eGFR at screening & albuminuria at baseline

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Adverse Events

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 Conclusions

• In patients with type 2 diabetes and kidney disease, the risk of kidney
failure and cardiovascular events was lower in the canagliflozin group
than in the placebo group at a median follow-up of 2.62 years

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Potential Role of SGLT2 Inhibition in Renoprotection

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CV safety trials are being conducted for each compound within the
newer classes
SAVOR-TIMI 531 OMNEON13 CAROLINA®11
(n = 16,492) (n = 4000) (n = 6000)
1,222 3P-MACE 4P-MACE ≥ 631 4P-MACE
EXAMINE2 TECOS4 CARMELINA12
(n = 5380) (n = 14,724) (n = 8300)
621 3P-MACE ≥ 1300 4P-MACE 4P-MACE + renal

2013 2014 2015 2016 2017 2018 2019 2021

ELIXA3 EXSCEL14 REWIND16

(n = 6068) SUSTAIN-67
(n = 3297) (n = 14,000) (n = 9622)
≥ 844 4P-MACE ≥ 1591 3P-MACE ≥ 1067 3P-MACE
3P-MACE
ITCA CVOT9 DECLARE-TIMI 5815
(n = 4000) (n = 17,150)
LEADER6 4P-MACE ≥ 1390 3P-MACE
DPP4 inhibitor
CVOTs (n = 9340) CANVAS10 CREDENCE17
≥ 611 3P-MACE (n = 4365) (n = 3700)
SGLT2 inhibitor ≥ 420 3P-MACE Renal + 5P-MACE
CVOTs EMPA-REG
OUTCOME®5 Ertugliflozin CVOT18
(n = 7034) CANVAS-R8
GLP1 CVOTs (n = 5700) (n = 3900)
≥ 691 3P-MACE HARMONY 3P-MACE
Albuminuria
Outcomes19
(n = 9400) 3P-MACE

Timings represent estimated completion dates as per ClinicalTrials.gov.

Adapted from Johansen. World J Diabetes 2015;6:1092–96.

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 Empagliflozin Dapagliflozin Canagliflozin
Therapeutic dose (mg/day) 10–25 5–10 100–300
Starting dose 10 10 100

Administration QD QD QD
With or without food With or without food Before first meal
Peak plasma concentration (hours
post-dose) 1.5 Within 2 1–2

Absorption
(mean oral bioavailability) ≥ 60% ~ 78% ~ 65%

Metabolism  Primarily glucuronidation - no active metabolite 

Elimination Hepatic:renal 43:57 Hepatic:renal 22:78 Hepatic:renal 67:33

(half-life, hours) [12.4] [12.9] [13.1]*

Selectivity over SGLT1 1:5000 > 1:1400 > 1:1601

Glucose excretion with higher dose
(g/day) 78 ~ 70 119

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 Renal Outcomes with Empagliflozin
Over 3.2 Years
EMPA-REG RENAL
(N=7020)
20 12
39%
18.8 10

Patients (%)
Patients (%)

15 P<0.001 44%
8 9.7
P<0.001
10 12.7 6
4 5.5
5
2
0 0
Incident or worsening nephropathy Post-hoc composite outcome*

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Patients (%)
15 38%
16.2 P<0.001
10 11.2
5

0
Progression to macroalbuminuria
Arrows = relative risk reduction.
*Doubling of SCr + eGFR ≤45 mL/min/1.73 m2, initiation of renal replacement therapy, or death from renal disease.
CI, confidence interval; eGFR, estimated glomerular filtration rate; SCr, serum creatinine.
Wanner C, et al. N Engl J Med. 2016;375:323-334. 25
 SAVOR-TIMI 531 EXAMINE2 TECOS3 CAROLINA®4 CARMELINA®5

Intervention Alogliptin/ Linagliptin/

Saxagliptin/ placebo Sitagliptin/ placebo Linagliptin/ placebo
placebo glimepiride

Main inclusion criteria

≥ 2 specified High risk of CV
ACS within 15–90
History of or multiple traditional CV risk events (e.g.
days before CVD
risk factors for CVD factors or manifest albuminuria, prior
randomisation
CVD CVD)

No. of patients 16,492 5380 14,671 6041 8300

Primary outcome 3P-MACE 3P-MACE 4P-MACE 4P-MACE 4P-MACE

Key secondary 3P-MACE; renal

outcome Expanded MACE 4P-MACE 3P-MACE 3P-MACE
composite

Target no.
of events 10406 650 1300 631 6257

Median follow-up (y)

2.1 1.5 3.0 6–7* 4*7

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