Two sodium glucose transporters, cause glucose reabsorption: SGLT-1 and SGLT-2. SGLT-2 is found in the proximal tubule of the kidney, accounts for 90% of the re-absorption of glucose. SGLT-1 is found in the gut and other tissues, account for glucose absorption On top of glycaemic lowering, SGLT2 inhibitors demonstrates additional clinical benefits versus placebo: Blood pressure lowering Weight loss Reduction in major cardiovascular events in patients with established cardiovascular disease1 The mechanisms responsible for the cardiovascular effects are currently unknown May be a combination of natriuresis, glycosuria (dual inhibition) and/or Na+/H+ exchange Ongoing mechanistic studies may provide answers A study published by Elsevier suggest that after 52 weeks of follow-up empagliflozin and dapagliflozin both groups showed significant reductions in HbA1c and FPG, but the reduction was greater in the empagliflozin group (P < 0.001). Hence, empagliflozin was more effective in reducing HbA1c and improving other cardiometabolic parameters than dapagliflozin

1. Dr. Vishal Gupta
Professor, Department of General Medicine,
SMS Medical College and attached Hospital, Jaipur

2.  Two sodium glucose transporters, cause glucose reabsorption: SGLT-1 and SGLT-2.
 SGLT-2 is found in the proximal tubule of the kidney, accounts for 90% of the re-
absorption of glucose.
 SGLT-1 is found in the gut and other tissues, account for glucose absorption
SGLT RECEPTORS

4. SGLT2 inhibition lowers the elevated renal
threshold for glucose in type 2 diabetes1
• Plasma glucose concentration: 10 mmol/L
• Plasma filtered: 180 L/day
• Glucose filtered: ~320 g/day
• Glucose excreted: ~70–119 g/day (equivalent to ~280–476 kcal/day)2-4
Glucose filtration
Loop of
Henle
SGLT2 SGLT1
Marked
increase in
glucose
excretion
Glomerulus Proximal tubule Distal tubule Collecting duct
SGLT: sodium–glucose co-transporter.
Figure adapted from: Bailey CJ. Trends Pharmacol Sci. 2011;32:63–71.
1. DeFronzo RA et al. Diabetes Obes Metab. 2012;14:5–14; 2. Invokana (canagliflozin). Summary of Product Characteristics; 3. Jardiance (empagliflozin). Summary of Product Characteristics;
4. Forxiga (dapagliflozin). Summary of Product Characteristics. All SmPCs available at: https://www.medicines.org.uk/emc/ (accessed April 2018).
Glucose
reabsorption
SGLT2
inhibitor

6. Multiple mechanisms may contribute to CV benefits
with SGLT2 inhibitors
Additional CV benefits
Increased
mitochondrial
calcium
Tubuloglo-
merular
feedback
Reduced
blood
pressure
Increased
uricosuria
Reduced
total
body fat
Reduced
HbA1c
Reduced
renal
damage
Reduced
arterial
stiffness
Ketone
utilisation
Reduced
preload
Increased
haematocrit
Reduced
plasma
volume
Na+/H+
exchanger2
Natriuresis1
Glycosuria1
SGL2
inhibitors
Reduced
glucotoxicity
&inflammation
Increased
oxygen
delivery
Reduced
myocardial
wall stretch
Reduce
oxidative
stress
Reduce
oxidative
stress

7.  SNS
activity (?)
 Weight
 Visceral
adiposity
 Blood pressure
 Arterial
stiffness
 Glucose
 Insulin
 Albuminuria
 Uric Acid
Novel
Pathways (?)
 LDL-C
 HDL-C
 Triglycerides
 Oxidative
stress
 SNS
activity (?)
SGLT2 inhibitors modulate a range of factors related to
CV risk: Based on clinical and mechanistic studies
SGLT 2 inhibitors exerts multiple role beside glycemic control

8. Known knowns or known unknowns: possible mechanisms
responsible for the benefits of SGLT2 inhibition
• On top of glycaemic lowering, SGLT2 inhibitors demonstrates
additional clinical benefits versus placebo:
– Blood pressure lowering
– Weight loss
– Reduction in major cardiovascular events in patients with established
cardiovascular disease1
• The mechanisms responsible for the cardiovascular effects are
currently unknown
– May be a combination of natriuresis, glycosuria (dual inhibition) and/or
Na+/H+ exchange
– Ongoing mechanistic studies may provide answers

9. Pharmacological properties of available SGLT2 inhibitors
Empagliflozin primarily excreted from kidney and liver
with lowest affection for SGLT1 receptors.
Empagliflozin Dapagliflozin Canagliflozin
Therapeutic dose (mg/day)
Starting dose
10–25
10
5–10
10
100–300
100
Administration QD
With or without food
QD
With or without food
QD
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
(half-life, hours)
Hepatic:renal 43:57
[12.4]
Hepatic:renal 22:78
[12.9]
Hepatic:renal 67:33
[13.1]*
Selectivity over SGLT1 1:5000 > 1:1400 > 1:1601
Glucose excretion with
higher dose (g/day)
78 ~ 70 119

10. Empaglifloazin have highest selectivity for SGLT2 receptor
Comparison of key pharmacological differences between
SGLT 2 INHIBITORS

12. Hospitalisation for heart failure
HR 0.65
(95% CI 0.50, 0.85);
p=0.002*
RRR for HHF is 35%; rates of HHF: 2.7% (empagliflozin) vs 4.1% (placebo); ARR for HHF is 1.4%
*Nominal p-value. Cumulative incidence function
ARR, absolute risk reduction; CV, cardiovascular; HHF, hospitalisation for heart failure; RRR, relative risk reduction
Zinman B et al. N Engl J Med 2015;373:2117
Heart failure outcome with SGLT2 inhibitors
1. ZinmanB et al.N EnglJ Med.2015;37:2117–2128.2. Neal B et al. N Engl J Med. 2017;377:644-657.
EMPA-REG OUTCOME study1
Adults with type 2 diabetes and established CV disease
CV death, non-fatal MI, or non-fatal stroke
Patients at risk:
Empagliflozin
Placebo
HR 0.86
(95.02% CI: 0.74, 0.99)
p<0.001 for non-inferiority
p=0.04 for superiority
Months
4687
2333
0
0
Patients
with
event
(%)
4580
2256
6
4455
2194
12
4328
2112
18
3851
1875
24
2821
1380
30
2359
1161
36
1534
741
42
370
166
48
5
10
15
20
Empagliflozin
Placebo
Hospitalization for heart failure and other adverse events were significantly
reduced in patients with empagliflozin as compared to placebo group.

13. EMPA-REG
OUTCOME®1
CANVAS2
CANVAS-R3 CREDENCE4 DECLARE-
TIMI 585
Ertugliflozin
CVOT6
Interventions Empagliflozin/
placebo
Canagliflozin/
placebo
Canagliflozin/
placebo
Canagliflozin/
placebo
Dapagliflozin/
placebo
Ertugliflozin/
placebo
Main
inclusion
criteria
Est. vascular
complications
Est. vascular
complications
or ≥ 2 CV risk
factors
Est. vascular
complications
or ≥ 2 CV risk
factors
Stage 2 or 3 CKD
+
macroalbuminuri
a
High risk for CV
events
Est. vascular
complications
No. of
patients
7034 4339 5700 3627 17,150 3900
Primary
outcome
3P-MACE 3P-MACE Progression of
albuminuria
ESKD,
S-creatinine
doubling,
renal/CV death
3P-MACE 3P-MACE
Key
secondary
outcome
4P-MACE Fasting insulin
secretion,
progression of
albuminuria
Regression of
albuminuria,
change in
eGFR
4P-MACE +
HHF
4P-MACE +
HHF +
revascularisatio
n
4P-MACE
Target no.
of events
691 ≥ 420 TBD TBD 1390 TBD
Estimated
median FU
~3 years 6–7 years 3 years ~4 years 4–5 years 5–7 years
Estimated
completion
2015 Apr 2017 2017 2019 2019 2021
Summary of CV outcome trials with SGLT2 inhibitors
13
Adapted from Inzucchi et al. Diabetes Vasc Dis Res 2015;12:90‒100. 1. Zinman et al. Cardiovasc Diabetol
2014;13:102.
2. NCT01032629. 3. NCT01989754. 4. NCT02065791. 5. NCT01730534. 6. NCT01986881.

14. Pooled data
-0.62
-0.74
-0.57
-0.48
-0.64
-0.46
-0.52
-0.68
-0.85
-0.64 -0.61 -0.59 -0.62
-0.68
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
Empagliflozin pooled Phase III placebo-corrected
change from baseline in HbA1c*
Pooled1 Monotherapy2
MET3 PIO4 MET + SU5
Insulin
78-week6 Mild RI7
Patients, n 831 821 224 224 217 213 165 168 225 216 169 155 98 97
BL HbA1c (%) 7.98 7.96 7.87 7.86 7.94 7.86 8.07 8.06 8.07 8.10 8.27 8.27 8.02 7.96
Adjusted
mean
(SE)
difference
vs
placebo
in
change
from
baseline
in
HbA
1c
(%)
†
†
†
†
†
†
Empagliflozin 10 mg QD Empagliflozin 25 mg QD
Reduction in the HbA1c level by empagliflozin was
significantly higher as compared to placebo and glycemic
control proportional to dose of empagliflozin.

15. 11.2
-11.0
-30
-20
-10
0
10
20
30
Empagliflozin versus glimepiride: Change from baseline in visceral and
subcutaneous fat at Week 104*
CI, confidence interval; EMPA, empagliflozin; H2H, head-to-head
*Dedicated sub-study using magnetic resonance imaging; patient participation was optional.
Ridderstråle M, et al. Lancet Diabetes Endocrinol. 2014;2:691‒700. Supplementary appendix.
Mean baseline (95% CI)
174.4
(143.3, 205.5)
156.7
(138.6, 174.8)
Mean
(95%
CI)
change
from
baseline
in
abdominal
visceral
adipose
tissue
(cm
2
)
Glimepiride
(n=34)
-22.2 cm2
(95% CI: -37.1, -7.4)
p=0.0039
Empagliflozin
(n=39)
17.7
-22.3
-40
-30
-20
-10
0
10
20
30
40
Mean baseline (95% CI)
337.0
(297.8, 376.1)
346.3
(312.5, 380.2)
Mean
(95%
CI)
change
from
baseline
in
subcutaneous
adipose
tissue
(cm
2
)
Glimepiride
(n=34)
-40.0 cm2
(95% CI: -58.9, -21.1)
p<0.0001
Empagliflozin
(n=39)

16. 215.1
6.4 16.4
176.3
5.0 10.7
167.1
4.5 10.8
0
50
100
150
200
250
Patients with any AE Patients with AE leading to
discontinuation
Patients with serious AE
Placebo (n = 3695)
Empagliflozin 10 mg QD (n = 3806)
Empagliflozin 25 mg QD (n = 4782)
n (%)
Placebo
(n = 3695)
Empagliflozin
10 mg QD
(n = 3806)
25 mg QD
(n = 4782)
Patients with any AE 2621 (70.9) 2686 (70.6) 3499 (73.2)
Patients with AE(s) leading to discontinuation
of trial drug
208 (5.6) 191 (5.0) 255 (5.3)
Patients with serious AE(s) 494 (13.4) 393 (10.3) 573 (12.0)
One or more severe AE(s) 324 (8.8) 258 (6.8) 373 (7.8)
Deaths 29 (0.8) 19 (0.5) 26 (0.5)
Rate
per
100
patient-years
Empagliflozin pooled safety and tolerability data:
Summary of adverse events
Overall adverse events was lowest with Empagliflozin 25 mg
followed by Empa 10 mg and placebo in increasing order.

17. Empagliflozin significantly reduces the incidence of nephropathy,
prevent progression to microalbuminuria, and prevent composite
renal failure

18. HbA1c reduction, weight loss, SBP reduction was significantly higher with Empa
25 mg, followed by Empa 10 mg and placebo in decreasing order

20. A study published by Elsevier
suggest that after 52 weeks of
follow-up empagliflozin and
dapagliflozin both groups showed
significant reductions in HbA1c and
FPG, but the reduction was greater
in the empagliflozin group (P <
0.001). Hence, empagliflozin was
more effective in reducing
HbA1c and improving other
cardiometabolic parameters than
dapagliflozin

21. A recent study suggest that empagliflozin causes a significant reductions
in fasting blood sugar as compared to dapagliflozin (P=0.001)

22. Thank you