Reno Cardio Protection in T2DM

Canagliflozin

Case Based Approach

 FDA Removes Boxed Warning About Risk of Amputations

• Based on review of new data from three clinical trials, FDA has removed the Boxed
Warning about amputation risk from canagliflozin
• Since its initial approval, canagliflozin has gained additional indications
• 2018: To reduce the risk of major adverse cardiovascular events (MACE) in adults
with type 2 diabetes and established CV disease
• 2019: To reduce the risk of ESKD, doubling of serum creatinine, CV death, and
hospitalization for heart failure (HHF) in adults with type 2 diabetes and diabetic
nephropathy with albuminuria

https://www.fda.gov/drugs/drug-safety-and-availability/fda-removes-boxed-warning-about-risk-leg-and-foot-amputations-diabetes-medicine-canagliflozin
accessed on 27th August 2020
 Significantly Enhanced Benefit of Canagliflozin
• FDA has acknowledged the significantly enhanced benefit of canagliflozin
• Safety information from recent clinical trials suggests that the risk of
amputation is lower than previously described
– Particularly when appropriately monitored
• Based upon these considerations, FDA has concluded that the Boxed
Warning should be removed

https://www.fda.gov/drugs/drug-safety-and-availability/fda-removes-boxed-warning-about-risk-leg-and-foot-amputations-diabetes-medicine-canagliflozin
accessed on 27th August 2020
 Patient Profile
Case #
58 years old female, housewife
Sedentary lifestyle
K/C/O T2DM since 7 years & on OAD’s
H/O hypothyroidism since 10 years
Questionable adherence
 Case : Clinical presentation & Examination
• Patient comes with c/o edema of both foot since last 6 months

• Dyspnea on severe exertion since last 3 months

O/E: BMI-28, pedal edema ++

P-68/min, BP- 134/78 mm of Hg

Systemic Examination: NAD

 Investigations
Parameters Results
FPG 158 mg/dL
PPBSL 230 mg/dl
HbA1c 8.2%
TG 123 mg/dL
HDL-C 54 mg/dL
LDL-C 67 mg/dL
BP 138/86 mm/Hg
eGFR 47.6 mL/min/1.73m2
Creatinine 1.6 mg/dL
 Current Medications

• Tab Metformin 1gm/Glimepiride 2mg

• Tab Thyroxine 100mcg

• Tab Atorvostatin 20mg

• Tab Clopidrogel 75mg

 Case: What are the treatment options?
ADA 2020 Guidance
1. Continue metformin as eGFR 47.6 ml/min/1.73m2 Progression of DKD
SGLT2 inhibitor Benefit
(Canagliflozin,
2. Add SGLT2i (Canagliflozin) as pt is elderly with Empagliflozin,
Dapagliflozin)
dyslipidaemia & for added renoprotection GLP1a Benefit
(Liraglutide)
DPP4i Neutral
3.DPP4i : glycaemic control (but no renoprotection) Insulin Neutral
SUs Neutral

4. Pioglitazone: glycaemic control (but no renoprotection

& weight gain)
References & Theory Support for the Case
 2017 Volume 70

Primary Care T2DM management

Beyond Glucocentricity- Focus on CV risk reduction

 Glycemic Control by Canagliflozin
Canagliflozin: Powerful Glycemic reduction Indian Real World
Evidence

Canagliflozin had highest reduction of 24.1% in FPG and 24.7% in PPG (p=0.001)
*p=0.002, compared to Dapagliflozin and Empagliflozin Vadgama J, Panikar V, Joshi SR, et al. Late Breaking Abstract #1137 presented at AACE 2017
 Weight Control
Weight & Glycemic effects of Canagliflozin
as Add-On to Metformin in T2 DM

Mean change in A1C: Baseline to 12 week Mean change in body weight: Baseline to 12 week

Canagliflozin significantly improved glycemic control & weight loss even with 50 mg dose.
Rosenstock J et al. DIABETES CARE, VOLUME 35, JUNE 2012
 Fat loss at various
tissues

Canagliflozin significantly reduced at 3 months

Visceral adipose Subcutaneous Epicardial adipose

tissue (VAT) adipose tissue (SAT) tissue (EAT)
(109 → 97 cm2) (193 → 177 cm2) (9.3 → 8.1 cm2)

2 to 6 kg weight loss is seen in clinical practice

1. What is % of HbA1c reduction with Canagliflozin after 6 months in your
practice?
Ans a) <0.5% b) 0.5-1% c) 1-1.5% d) >1.5%

2. What is your experience of weight loss due to Canagliflozin in DM patients

after 6 months?
Ans. a) 1-3kg b) 3-5kg c) >5kg
 DKD Shortens Life
Diabetic Span by 16 Years
Nephropathy
among native 6 • Early CKD
ye
Asian-Indians ars
• Diabetic nephropathy is one of
the leading causes of chronic 10 • Diabetes
renal failure in India. It has ye
been reported that among ars
4837 patients with chronic
renal failure seen over a period 16 • Early DKD
of 10 years, the prevalence of ye
ars
diabetic nephropathy was
30.3%.
Vijay Viswanathan, Nephrology Dialysis Transplantation, Volume 14, Issue
12, December 1999, Pages 2805–2807,
Wen CP, et al. Kidney Int. 2017;92(2):388-396.
 USFDA
DCGI
CREDENCE: ESC/EASD Additional
CREDENCE ADA ASN ADA 2020 Additional
Primary Guideline Indication ACC
April 14, Update November December Indication
Prevention August Approval
2020 June 2019 2019 2019 Approval March 2020
July 2019 2019 September
March 2020
2019

One Year Milestone of CREDENCE

 Higher Renal Risk Population in CREDENCE
Median
Albuminuria categories (mg/g) Mean eGFR UACR
(mL/min/1.73 m2) (mg/g)
A1: <30 A2: 30-300 A3: >300

≥90 D DECLARE 85 13
C CANVAS Program 76 12
(mL/min/1.73 m2)

D
GFR categories

60-90 C E
E EMPA-REG OUTCOME 74 18
45-59 CREDENCE 56 927
30-44
Sustained RRT Events
<30
DECLARE Not reported
CANVAS Program 18
Low
Moderately High Very high EMPA-REG OUTCOME 11
increased
CREDENCE 176

Participants with an event (%)
Participants with an event
CREDENCE: 30% reduction of Primary Outcome
(ESKD, Doubling of Serum Creatinine, or Renal or CV Death)
25
Hazard ratio, 0.70 (95% CI, 0.59–0.82) 340 participants

P = 0.00001
20

245 participants
15
(%)

10

5 Placebo
Canagliflozin
0
0 26
6 52
12 78
18 104
24 130
30 156
36 182
42
Months since randomization
No. at risk
Placebo 2199 2178 2132 2047 1725 1129 621 170
Canagliflozin 2202 2181 2145 2081 1786 1211 646 196

Perkovic V, et al. N Engl J Med. 2019;380(24):2295-2306.

 Canagliflozin prevents decline of eGFR
Canagliflozin Placebo
Baseline 56.4 56.0
0
m 2)
change (SE) in

-2 60% reduction in the rate of eGFR

decline with canagliflozin
(mL/min/1.73
LS Mean Change (±SE)

-4
eGFR (mL/min/1.73

-6 –1.85/year
-8
-10
m2)

-12
–4.59/year
mean

-14 Chronic eGFR slope

LSeGFR

-16 Difference: 2.74/year (95% CI, 2.37–3.11)

-18
in

0 26
6 52
12 78
18 104
24 130
30 156
36 182
42
Months since randomization
No. of Participants
Placebo 2178 2084 1985 1882 1720 1536 1006 583 210
Canagliflozin 2179 2074 2005 1919 1782 1648 1116 652 241
On treatment

Perkovic V, et al. N Engl J Med. 2019;380(24):2295-2306.

 Projected Effects on eGFR

60 Average CREDENCE patient

50 Age = 63 years
eGFR = 56
40
eGFR

30

20

10
eGFR < 10 mL/min/1.73 m2
0
0 5 10 15 20 25 30
Years

Perkovic V. NEJM. 2019 10.1056/NEJMoa1811744.

 Renal protection by Canagliflozin
Canagliflozin: Reduction of eGFR decline & need of Dialysis

60 Average CREDENCE
50
patient
–1.8 Age = 63 years
40 –4 5/y eGFR = 56
.5 e
eGFR

30 9/ ar
20
ye
Average ar 15.1 years
patient would 10
delay develop eGFR < 10 mL/min/1.73 m2
0
eGFR 10 by 0 5 10 15 20 25 30
over 15 years Years
Placebo/SOC Canagliflozin
by taking Age = 73 years Age = 88 years
Canagliflozin eGFR = 10 eGFR = 10

Perkovic V. NEJM. 2019 10.1056/NEJMoa1811744.

 Multiple mechanisms for Renoprotection

Intraglomerular pressure
Glucose Albuminuria

BP/arterial
Oxidant stress
stiffness Intrarenal
Volume Natriuresis
angiotensinogen
upregulation
Inflammation/
fibrosis Renal
Improved oxygenation
Efficiency of substrate
autophagy utilization
Beneficial Effects of Canagliflozin on eGFR in Participants with Baseline eGFR <30
mL/min/1.73 m2
Canagliflozin Placebo 43.0% reduction in the rate of
Mean baseline, mL/min/1.73 m 2
26.3 26.5 eGFR decline with canagliflozin
35 from Week 3 to end of study

Mean eGFR (mL/min/1.73 m2)

30

25
P = 0.003
20

15

10
Acute eGFR slope*
5 Difference: –0.88 mL/min/1.73 m2 (95% CI: –3.16, 1.39)
Chronic eGFR slope†
Difference: 2.54 mL/min/1.73 m2/year (95% CI: 0.9, 4.17)
0 0 20 40 60 80 100 120 140 160 180
0 3 13 26 52 78 104 130 156 182
Weeks since randomization
Canagliflozin, n 82 82 77 78 71 57 50 36 22 7
Placebo, n 89 88 85 81 76 65 59 33 21 8

*Measured from baseline to Week 3.

†
Measured from Week 3 until the end of the study.
 Benefits of Canagliflozin in Renal Outcomes in Participants with Baseline
eGFR <30 mL/min/1.73 m2
Participants with an
Number of participants
event per 1000
with an event
patient-years
Canagliflozin Placebo Canagliflozin Placebo9.5 HR (95% CI)
ESKD, doubling of serum creatinine, or renal or CV death
8.5
Overall 245 340 43.2 61.2 7.5
0.70 (0.59, 0.82)
eGFR <30 mL/min/1.73 m2 23 29 115.4 134.5 6.5
0.88 (0.51, 1.52)
ESKD, doubling of serum creatinine level, or renal death 5.5
Overall 153 224 27.0 40.4 4.5
0.66 (0.53, 0.81)
eGFR <30 mL/min/1.73 m2 17 25 85.6 115.9 3.5
0.76 (0.41, 1.40)
Dialysis, kidney transplantation, or renal death 2.5
Overall 78 105 13.6 18.6 1.5
0.72 (0.54, 0.97)
eGFR <30 mL/min/1.73 m2 10 14 48.4 61.8 0.5 0.90 (0.39, 2.07)
0.25 0.5 1.0 2.0 4.0

Favors Favors
Canagliflozin Placebo

Benefits seen in Renal outcomes favors Canagliflozin

3. What is the eGFR (ml/min/1.73 sq m2) level in DKD patients where you have
used Canagliflozin?
Ans a) >45ml b) 30-45ml c) <30ml

4. Which SGLT2i do you prefer for DKD?

Ans. a) Canagliflozin b) Dapagliflozin c) Empagliflozin
 Regulatory
Sep 2019: USFDA Approvals
Indication to reduce the risk of ESKD,
doubling of serum creatinine, CV death,
and HHF in adults with T2DM and diabetic
nephropathy with albuminuria >300
mg/day.
Continuation of therapy in patients with
eGFR ≤30 mL/min/1.73 m2 and
albuminuria >300 mg/day until initiation
of dialysis .
Mar 2020: DCGI Approval
To reduce the risk of end stage kidney
disease (ESKD), doubling of serum
creatinine, cardiovascular (CV) death,
and hospitalization for heart failure in
adults with type 2 diabetes mellitus
and diabetic nephropathy with
albuminuria >300mg/day
DKD patients: NNT for Renal Outcomes Over 2.5 Years

Primary composite ESKD, doubling of serum ESKD

outcome creatinine, or renal death

22 28 43
MACE (CV Death, MI, or Stroke) reduction in DKD patients
Participants with an event (%) 25
Hazard ratio, 0.80 (95% CI, 0.67–0.95) Placebo
P = 0.01 Canagliflozin
20
20% Reduction
with Cana
269 participants
15
217 participants
10

0
0 26
6 52
12 78
18 104
24 130
30 156
36 182
42
Months since randomization
No. at risk
Placebo 2199 2152 2100 2022 1717 1143 635 168
Canagliflozin 2202 2163 2106 2047 1756 1196 642 198
 Renal and CV Outcome Benefits in DKD patients
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
CV death or hospitalization for heart failure 0.69 (0.57–0.83) <0.001
CV death, MI, or stroke 0.80 (0.67–0.95) 0.01
Hospitalization for heart failure 0.61 (0.47–0.80) <0.001
ESKD, doubling of serum creatinine, or renal death 0.66 (0.53–0.81) <0.001

0.25 0.5 1.0 2.0 4.0

Favors Canagliflozin Favors Placebo

Perkovic V, et al. N Engl J Med. 2019;380(24):2295-2306.

Case # After 24 weeks of adding Canagliflozin 100mg
• HbA1c : 8.2% to 7.3%

• FPG : 158 to 130 mg/dl

• PPBG : 230 to 180 mg/dl

• Creatinine: 1.6 to 1.5 mg/dl

• eGFR: 47.6 to 48.9 mL/min/1.73m2

Uniqueness of Canagliflozin
CANA
Glycemic control +++
Weight control +++
Primary prevention data in T2DM YES
Primary Prevention data in DKD YES
USFDA approval in DKD YES
DCGI approval in DKD YES
THANK YOU!