Renal benefit of Empagliflozin

1. SGLT2 inhibitors are unique in that they are the only class of drug that
is insulin independent
• Oral medications used for treating type 2 diabetes.
SGLT2 Inhibitors work in the following ways:
• ↓Glucose absorption in the kidneys → Passed out in the urine.
• Reducing the amount of glucose in your blood.

2. Urinary glucose excretion via SGLT2 inhibition
2
1. Bakris et al. Kidney Int 2009;75;1272–7.
SGLT2
SGLT2
inhibitor
SGLT1
SGLT2 inhibitors
reduce glucose
reabsorption
in the proximal
tubule, leading to
urinary glucose
excretion* and
osmotic diuresis
Filtered glucose load >
180 g/day

3. According to ADA’18-
Empagliflozin is the only oral anti-diabetic drug that reduces
cardiovascular morbidity and mortality rate
(EMPA-REG OUTCOME Trial )
This additional benefit makes it different/Unique from other
SGLT-2 inhibitors
Very recently SGLT-2 inhibitors, Empagliflozin showes improved
renal outcomes in diabetic patients, in the landmark EMPA-REG
OUTCOME trial. So FDA granted fast-track designation for
Empagliflozin in chronic kidney disease

4. 38 39
44
55
Progression to
macroalbuminuria
Incident or
Worsening
nephropathy
Doubling of serum
creatinine
Initiation of renal
replacement
therapy
Study design: EMPA-REG
OUTCOME clinical trials;
Number of patients: 7020;
Study Duration: 3.1 years weeks
Reduces clinically relevant renal events
Result: Empagliflozin showed improved renal outcomes.

5. Glucoseand the kidney
This chapter will be much larger in the next edition of
“The
Kidney”

6. 1. Gluconeogenesis (cortex) mainly for utilization in the medulla
• Fasting post-absorptive state:
• 20-25% of the glucose released into the circulation is derived from
the kidneys (12-55g)
• Kidneys use about 10% of the entire glucose pool (25-35g)
• Post-prandial state (4-5 hours after a meal):
• Kidneys responsible for 60% of endogenous glucose release (70g)
• Renal release of glucose x30% in pts with T2D
2. Reabsorption of filtered glucose by the proximal tubule
• GFR of 125 ml/min x 90-100 mg/dL = 160-180g filtered
• Nearly all of it is reabsorbed
• Primary renal contribution to glucose homeostasis
DOI:
10.1152/ajpendo.00116.2001
DOI: 10.1113/JP271904
DOI:
10.1016/j.diabres.2017.07.033
DOI:
10.1152/physrev.00055.2009
DOI:10.1016/j.tips.2010.11.011
DOI:
10.1016/j.metabol.2014.06.018
Roleof the kidneyinglucose homeostasis

7. 7
Brief Review of Kidney Role in
Glucose Homeostasis

8. 8
Kidney Plays a Significant Role in Glucose Balance
1. Diabetes Med 2010; 27(2):136-42 , 2. J Intern Med 2007; 261(1):32-4
Reabsorption¹
Utilization¹
Production¹
(gluconeogenesis)
Kidney
Utilizes ~25-30 g/day
Produces ~15-55 g/day
Glucose in diet
~180 g/day ²
Glucose Utilization
~250 g/day ²
Rest of body
~125 g/day
Brain
~125 g/day
Filtration &
Reabsorption
~180 g/day
~70 g/day
Produced by
gluconeogenesis
or glycogenolysis
20% is produced
by the kidney

9. Glucose Transporters
• Glucose is essential for energy production in
the living body.
• Glucose transporters play a critical role in
various organs.
• They are classified into two families¹ʼ²:
• facilitative glucose transporters (GLUTs)
• sodium-dependent glucose transporters
(SGLTs)
• SGLTs 1-6: active energy dependent glucose
transporters¹ʼ²
• SGLT1: low capacity, high affinity, mostly
in intestine
• SGLT2: high capacity, low affinity, mostly
in kidney
1. Diabetes Ther. 2013; 4(2): 195–220, 2. J Clin Endocrinol Metab. 2010; 95(1):34-42
9

10. 10
Empagliflozin Mechanism of Action

11. Renal glucose re-absorption in healthy individuals
Filtered glucose load
180 g/day¹
SGLT1
SGLT2
~ 10%
~ 90%
1. Diabet Med. 2010; 27(2):136-42
11

12. Renal glucose re-absorption in patients with diabetes
SGLT1
SGLT2
~ 10%
~ 90%
Filtered glucose load >
180 g/day¹
12
1. Diabet Med. 2010; 27(2):136-42

13. Urinary glucose excretion via SGLT2 inhibition
SGLT2
SGLT2
inhibitor
SGLT1
SGLT2 inhibitors reduce
glucose re-absorption
in the proximal tubule,
leading to urinary
glucose excretion* and
osmotic diuresis¹
Filtered glucose load
> 180 g/day
*Loss of ~ 80 g of glucose/day
13
1. Diabet Med. 2010; 27(2):136-42

14. 14
Expected Clinical Effects of SGLT2 Inhibition
Abdul-Ghani MA, et al. Endocri Rev. 2011; 32:S15-S31.
Loss of calories
Reduced sodium
load
Reduced glycemia
HbA1c
Reduction
0.6 - 1%
Weight loss
2 – 3 kg
BP reduction
3 – 5 mmHg
Increased glucose
excretion
Increased sodium
excretion

15. Renal Protection Mechanism
of Empagliflozin

19. Renal handling of glucose in non-diabetic individuals
Glomerulus
Loop
of Henle
Distal
tubule
Collecting
duct
Proximal
tubule
S3 segment of proximal tubule
- ~10% glucose reabsorbed
- Facilitated by SGLT1
S1 segment of proximal tubule
- ~90% glucose reabsorbed
- Facilitated by SGLT2
Glucose
reabsorption
S3
~10%
S1
~90%
Blood &
glucose
(180 L/day)
(1000 mg/L)
=180 g/day
No/minimal
glucose
excretion
19

20. Renal SGLT2 Inhibition A Novel Approach to Type 2 Diabetes
Adapted from:
1. Chao EC & Henry RR. Nature Reviews Drug Discovery 2010;9:551-559.
2. DeFronzo RA, et al. Diab Obes Metab 2012;14:5-14.
3. Washburn WN. J Med Chem 2009;52:1785-1794.
Patients with type 2 diabetes
Urinary
excretion
Glucose
Excess
glucose
Glomerulus
Renal
proximal
tubule
Glucose
reabsorption
Type 2 diabetes with SGLT2 inhibition
Renal proximal tubule
Glucose excretion
Excess
glucose
Glomerulus
Glucose
excretion
enabled through
SGLT2 inhibition
Reduced blood
glucose levels
resulting from
less glucose
reabsorption
20

22. Cardio & renal
Protection of
SGLT2

24. Cardio & renal
Protection of SGLT2

29. SGLT2 inhibitors significantly lower
progression of kidney disease by
• Reducing intraglomerular pressure &
• Improving hyperfiltration.

30. Study Analysis

31. 31
EMPA-REG RENAL®

32. 1. N Engl J Med 2016; 375:323-334
32

33. Renal Outcomes with Empagliflozin over 3.2 Years (EMPA-REG RENAL)¹
18.8
12.7
0
2
4
6
8
10
12
14
16
18
20
Incident or worsening
nephropathy
9.7
5.5
0
2
4
6
8
10
12
Post-hoc composite outcome*
16.2
11.2
0
2
4
6
8
10
12
14
16
18
Progression to
macroalbuminuria
Patients
(%)
Patients
(%)
Patients
(%)
39%
P<0.001
46%
P<0.001
38%
P<0.001
Arrows = relative risk reduction
*Doubling of SCr + eGFR ≤45 mL/min/1.73 m2, initiation of renal replacement therapy, or death from renal disease.
33
1. N Engl J Med 2016; 375:323-334

34. SGLT2 Inhibitors Induce a Temporary Reduction in eGFR, but Preserve
Renal Function Overtime¹
1-Wanner C et al,. Empagliflozin and progression of kidney disease in type 2 diabetes. New England Journal of Medicine. 2016; 28;375(4):323-34. 34

35. 35
The EMPEROR-Reduced trial

36. Inclusion criteria¹
EF% NT-proBNP (pg/ml)
Patients without AF
NT-proBNP (pg/ml)
Patients with AF
≥36 to ≤40 ≥2500 ≥5000
≥31 to ≤35 ≥1000 ≥2000
≤30 ≥600 ≥1200
˃ 40+HHF within 12 months ≥600 ≥1200
Key inclusion criteria:
• NYHA class II-IV
• Elevated NT-pro BNP
• Guideline recommendation
medication stable ≥1 week
prior to first visit
• eGFR ≥20 ml/min/1.73 m2
The study included patients with Chronic HF with reduced ejection fraction
NYHA; New York Heart Association
1-N. Engl. J. Med 2020.8;383(15)1413-1424
.

37. Effect on individual components of the primary endpoint¹
31%
8%
25%
1-N. Engl. J. Med 2020.8;383(15)1413-1424

38. Empagliflozin Reduced eGFR Significantly Slower Over the Time vs
Placebo¹
 Empagliflozin was associated with a slower progressive decline in renal function in patients with chronic HF
and a reduced EF, regardless of the presence or absence of diabetes².
–2.28 ml / min / 1.73
m2 / year
On placebo
– 0.55 ml /min/1.73 m2
/ year
On Empagliflozin
1.73 ml / min / 1.73 m2
/ year
P ˂ 0.001
1-N. Engl. J. Med 2020. 8;383(15):1413-1424

39. Empagliflozin reduced composite renal endpoint by 50%¹
1-https://www.radcliffecardiology.com/emperor-reduced-milton-packer-harriette-van-spall
 a composite renal outcome (chronic dialysis or renal transplantation or a profound, sustained
reduction in the estimated GFR) occurred in 30 patients (1.6%) in the empagliflozin group and in 58
patients (3.1%) in the placebo group (hazard ratio, 0.50; 95% CI, 0.32 to 0.77)
50%
30 on Empagliflozin
58 on Placebo
HR= 0.50 (0.32-0.77)