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1. Outline
Anatomy and Physiology
Diabetes Mellitus Basics
Treatment of Diabetes Mellitus
SGLT2
• Pharmacology
• Clinical Overview
• SGLT2 differences
• Place in Therapy
Dapagliflozin
Take Home Message

2. ADA :
Diagnostic
criteria
2
Test Prediabetes
HbA1c 5.6 to 6.4 %
Fasting glucose 100 to 126
mg/dL
2-hour glucose 140 to 199
mg/dL

3. Treatment
goals
3
American Diabetes Association (ADA)
American Association of Clinical Endocrinology (AACE) American College of Physicians (ACP)

4. Class Example MOA Advantages Disadvantages
Biguanides Metformin Decreases hepatic glucose
production+++ , Improves
insulin sensitivity+
No hypoglycemia
Better HBA1C reduction
Decreased CVD risk
Vitamin B12 def.
GI side effects
Not recommended in renal
failure
Sulphonyl ureas Glimepride Increases insulin secretions Better HBA1C reduction
Decreased CVD risk
Hypoglycemia , weight
gain
TZD Pioglitazone Increases insulin sensitivity
+++
No hypoglycemia
Better HBA1C reduction
Decreased CVD risk
Improves lipid profile
Weight gain
Edema
Heart failure
Bone fracture
DPP4 inhibitors Teneligliptin and
Vildagliptin
Increases insulin secretions
Decreases glucagon
secretions
Slows gastric emptying
Increases satiety
No hypoglycemia
Better HBA1C reduction
Immune related skin
reactions
GLP1 receptor
agonist
Liraglutide Increases insulin secretions
Decreases glucagon
secretions
Slows gastric emptying
Increases satiety
No hypoglycemia
Decreases weight
Better HBA1C reduction
Decreased CVD risk
Injectable
GI side effects
Pancreatitis
Increases heart rate
SGLT2 inhibitor Dapagliflozin Blocks the reabsorption of
glucose in kidney
No hypoglycemia
Decreased weight
Decreased blood pressure
UTI
Dehydration
Not recommended in renal
failure

5. 5

6. 1st line : Metformin, Lifestyle
modification (weight reduction and
physical activity )
CVD or CKD and HF
GLP-1RA Either/ Or SGLT2i (if GFR
is adequate)
HbA1c above target
Consider adding other class with
CVD benefit : DPP4i (If not on GLP-
1RA) or Basal Insulin or SU or TZD
ADA 2019
Diabetes Care Volume 42, Supplement 1, January 2019
6

7. 1st line : Metformin,
Lifestyle modification
and (weight reduction
and physical activity )
Compelling need to
minimize the
hypoglycemia
Compelling need to
minimize the weight
gain or promote the
weigh loss
Cost is a major issue
No established CVD
and CKD
ADA 2019
Diabetes Care Volume 42, Supplement 1, January 2019
7

8. 1st line : Metformin, Lifestyle
modification and (weight
reduction and physical
activity )
Compelling need to
minimize the hypoglycemia
No established CVD and
CKD
ADA 2019
Diabetes Care Volume 42, Supplement 1, January 2019
8

9. 1st line : Metformin, Lifestyle
modification and (weight
reduction and physical
activity )
Compelling need to
minimize the weight gain or
promote the weigh loss
No established CVD and
CKD
ADA 2019
Diabetes Care Volume 42, Supplement 1, January 2019
9

10. 1st line : Metformin, Lifestyle
modification and (weight
reduction and physical
activity )
Cost is a major issue
No established CVD and
CKD
ADA 2019
Diabetes Care Volume 42, Supplement 1, January 2019
10

11. Why do we need
Sodium-glucose
transport protein 2
(SGLT2) inhibitors?
11

12. 12
Can J Cardiol . 2018 May;34(5):575-584

13. . Cureus 13(8): e16868. DOI 10.7759/cureus.16868

14. • Diabetic nephropathy : affects
∼40% of type 1 and type 2
diabetic patients (Diabetes
Care 2005 Jan; 28(1): 164-176.)
14
Molecules . 2019 Aug 6;24(15):2857 . Cureus 13(8): e16868. DOI 10.7759/cureus.16868

16. SGLT2
inhibitors
MOA
16
180g /per day or 125 mg per min glucose is
filtered
Meaning all filtered glucose is reabsorbed with
none present in the urine.
Poorly managed diabetes mellitus, the filtered
glucose load surpasses the reabsorptive
capacity of the kidney, causing glycosuria.
In healthy individuals, no glycosuria appears
until blood glucose levels exceed 180 mg/dl,
referred to as the threshold for glycosuria [22].
. Cureus 13(8): e16868. DOI 10.7759/cureus.16868

17. SGLT2
inhibitors
MOA
17
The pharmacodynamic effect of
SGLT2 inhibitors is inducing
glycosuria by
• lowering the threshold for glucose
reabsorption
•
Dapagliflozin, for example,
reduced TmG by 56% in well-
controlled T2DM patients (from
420 mg/min to 184 mg/min)
. Cureus 13(8): e16868. DOI 10.7759/cureus.16868

18. SGLT2
inhibitors
• Sodium Glucose cotransporters (SGLTs) are
proteins that occur primarily in the kidneys
• SGLT1 and SGLT2 are the two most known
SGLTs of this family.
• SGLT2 is the major transport protein and
promotes reabsorption from the glomerular
filtration glucose back into circulation and is
responsible for approximately 90% of the kidney's
glucose reabsorption
• SGLT2 is mainly expressed in the kidneys on
the epithelial cells lining the first segment of the
proximal convoluted tubule.
• By inhibiting SGLT2, gliflozins prevent the
kidneys' reuptake of glucose from the glomerular
filtrate and subsequently lower the glucose level
in the blood and promote the excretion of glucose
in the urine (glucosuria)
18

19. Dapagliflozin
Description
19
Inhibits subtype 2 of the sodium-
glucose transport proteins
(SGLT2) which are responsible for
at least 90% of the glucose
reabsorption in the kidney.
The IC50 for SGLT2 is less than
one thousandth of the IC50 for
SGLT1 (1.1 versus 1390 nmol/L),
so that the drug does not interfere
with intestinal glucose absorption

20. Dapagliflozin
Milestones
20
Developed by Bristol-Myers Squibb in partnership
with AstraZeneca
Approved by EU-2012 and USFDA-2014
India
• CDSCO approval in 2015
• Nov 2011 , Indian court rejects the patent of Dapagliflozin , making it available
for generic companies
Approved combinations
• Dapagliflozin + Metformin (US FDA & CDSCO)
• DPP4i + Dapagliflozin with or without Metformin (Approved by US FDA and
under approval with CDSCO)
2020 : US FDA approved it in HFrEF (First drug in SGLT2i to
get approval for NYHA class 2-4 HFrEF)
2021: US FDA approved it in adults with chronic kidney disease
at risk of progression.

21. Pharmacolo
gy of SGLT2
Inhibitors
(Dapagliflozi
n)
21
Sodium-glucose cotransporter 2 inhibitor
Reabsorption of approximately 90% of the urinary glucose
in the proximal tubule of the nephron.
Induces glucosuria
Enhance natriuresis,
Lower systolic blood pressure and reduce body mass
Early decreases in systolic blood pressure, weight and
estimated glomerular filtration rate (eGFR
Increase in hematocrit
Therapeutics and Clinical Risk Management 2021:17 823–830

22. 22

23. 23
Chaurasia P, Dholariya S, Kotadiya F, et al. (September 26, 2021) A New Hope in Type 2 Diabetes Mellitus Management: Sodium-Glucose
Cotransporter 2 Inhibitors. Cureus 13(9): e18300. DOI 10.7759/cureus.18300

24. Dapagliflozin as a monotherapy in
T2DM
Dapagliflozin as monotherapy
Six randomized controlled trials
(RCTs) including 2033 patients
NA
Reduction in glycosylated hemoglobin A1c (HbA1c) (weighted
mean difference [WMD]: -0.60%; 95% confidence interval [CI]: -
0.67%, -0.52%; P < .00001)
Fasting plasma glucose (FPG) (WMD: -1.30 mmol/L; 95% CI: -
1.52, -1.08; P < .00001), and body weight (WMD: -1.50 kg; 95%
CI: -1.67, -1.32; P < .00001).
Increased risk of urinary tract infections (relative risk [RR]: 1.74;
95% CI: 1.21, 2.49; P = .003) and genital tract infections (RR:
3.52; 95% CI: 2.06, 6.03; P < .00001).
Dapagliflozin monotherapy was well tolerated and
effective in reducing the level of HbA1c, FPG, and
body weight in patients with T2DM without increasing
hypoglycaemia, although it may increase the risk of
urinary tract infections and genital tract infections
Title: Efficacy and safety of dapagliflozin as monotherapy in patients with type 2
diabetes mellitus: A meta-analysis of randomized controlled trials
Ref: Medicine (Baltimore). 2019 Jul;98(30):e16575
Key massage: Dapagliflozin as a monotherapy in T2DM reduces HbA1c by 0.6%

25. Treatment-naïve patients with
HbA1c 7.5-12%.
Dapagliflozin plus metformin,
dapagliflozin alone and metformin
alone.
Study 1 & 2: Dapa + Met (n=194,
211), Dapa + Placebo (n=203,219),
Met + Placebo (n=201,208)
24-week
reductions in HbA1c compared with either monotherapy: -2.05 for
dapagliflozin + metformin, -1.19 for dapagliflozin, and -1.35 for
metformin (p < 0.0001) (Study 1)
-1.98 for dapagliflozin + metformin, -1.45 for dapagliflozin and -
1.44 for metformin (p < 0.0001) (Study 2). Combination therapy
was statistically superior to monotherapy in reduction of FPG (p <
0.0001 for both studies); combination therapy was more effective
than metformin for weight reduction (p < 0.0001).
In treatment-naïve patients with T2D, dapagliflozin
plus metformin was generally well tolerated and
effective in reducing HbA1c, FPG and weight.
Dapagliflozin-induced glucosuria led to an increase in
events suggestive of urinary tract and genital
infections
Title: Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2
diabetes, a randomised controlled trial
Ref: Int J Clin Pract. 2012 May;66(5):446-56.
Key massage: In treatment-naïve patients with T2D, dapagliflozin plus metformin reduced HbA1c
by -1.98 to -2.05 %

26. Who have inadequate glycaemic
control with metformin.
3 doses of dapagliflozin (2.5 mg,
n=137; 5 mg, n=137; or 10 mg,
n=135) or placebo (n=137) orally
once daily
546 adults with type 2 diabetes
24-week
At week 24, mean HbA(1c) had decreased by -0.30%
(95% CI -0.44 to -0.16) in the placebo group, compared
with -0.67% (-0.81 to -0.53, p=0.0002) in the
dapagliflozin 2.5 mg group, -0.70% (-0.85 to -0.56,
p<0.0001) in the dapagliflozin 5 mg group, and -0.84%
(-0.98 to -0.70, p<0.0001) in the dapagliflozin 10 mg
group
Addition of dapagliflozin to metformin provides a new
therapeutic option for treatment of type 2 diabetes in
patients who have inadequate glycaemic control with
metformin alone.
Title: Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control
with metformin: a randomised, double-blind, placebo-controlled trial
Ref: Lancet. 2010 Jun 26;375(9733):2223-33
Key massage: Inadequate glycaemic control with metformin ,add on Dapagliflozin reduces HbA1c by – 0.70%
to -0.84%

27. Inadequately controlled with
metformin monotherapy (baseline
mean HbA1c, 7.7 %)
Type 2 diabetes, who were
receiving metformin monotherapy,
to add-on dapagliflozin (n = 406) or
glipizide (n = 408)
Dapagliflozin (n = 406) or glipizide
(n = 408)
52-week
HbA1c reduction with dapagliflozin (-0.52 %) compared with
glipizide (-0.52 %) at 52 weeks
Dapagliflozin produced significant adjusted mean weight loss (-
3.2 kg) versus weight gain (1.2 kg; P < 0.0001) with glipizide,
significantly increased the proportion of patients achieving ≥ 5 %
body weight reduction (33.3 %) versus glipizide (2.5 %; p <
0.0001), and significantly decreased the proportion experiencing
hypoglycemia (3.5 %) versus glipizide (40.8 %; p < 0.0001).
Despite similar 52-week glycemic efficacy,
dapagliflozin reduced weight and produced less
hypoglycemia than glipizide in type 2 diabetes
inadequately controlled with metformin
Title: Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have
inadequate glycemic control with metformin
Ref: Dtsch Med Wochenschr. 2013 Apr;138 Suppl 1:S6-15
Key message: Dapagliflozin reduced weight and produced less hypoglycemia than glipizide

28. Patients with uncontrolled T2DM on
glimepiride
Adult patients (n = 597) were
randomly assigned to placebo or
dapagliflozin (2.5, 5 or 10 mg/day)
added to open-label glimepiride 4
mg/day for 24 weeks.
n = 597
24-week
HbA1c adjusted mean changes from baseline for
placebo versus dapagliflozin 2.5/5/10 mg groups
were -0.13 versus -0.58, -0.63, -0.82%, respectively
(all p < 0.0001 vs. placebo by Dunnett's procedure).
Corresponding body weight and fasting plasma
glucose values were -0.72, -1.18, -1.56, -2.26 kg and
-0.11, -0.93, -1.18, -1.58 mmol/l, respectively.
Dapagliflozin added to glimepiride in patients with
T2DM uncontrolled on sulphonylurea monotherapy
significantly improved HbA1c, reduced weight and
was generally well tolerated,
Title: Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control
with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial
Ref: Diabetes Obes Metab. 2011 Oct;13(10):928-38
Key message: Dapa + Glimepiride significantly improved HbA1c, reduced weight and was generally well tolerated

29. Inadequately controlled with
metformin and sulfonylurea.
Dapagliflozin 10 mg/day (n = 109)
or placebo (n = 109) for 24 weeks.
n = 218
24-week
HbA1c significantly improved from baseline with dapagliflozin
(placebo-subtracted change -0.69% [-7.5 mmol/mol], P < 0.0001;
-33.5 mg/dL [-1.86 mmol/L], P < 0.0001, respectively).
More patients achieved a therapeutic glycemic response (HbA1c
<7.0% [53 mmol/mol]) with dapagliflozin (31.8%) versus placebo
(11.1%) (P < 0.0001).
Body weight and systolic blood pressure were significantly
reduced from baseline over 24 and 8 weeks, respectively, with
dapagliflozin (placebo-subtracted change -2.1 kg, P < 0.0001; -
3.8 mmHg, P = 0.0250).
Dapagliflozin was well tolerated and effective over 24
weeks as add-on to metformin plus sulfonylurea.
Adverse effects included hypoglycemia and genital
infections.
Title: Dapagliflozin improves glycemic control and reduces body weight as add-on therapy to
metformin plus sulfonylurea: a 24-week randomized, double-blind clinical trial
Ref: Diabetes Care 2015 Mar;38(3):365-72
Key message: Dapa + Met + Glimepiride well tolerated and effective

30. Inadequately controlled on
pioglitazone.
Patients previously receiving
pioglitazone ≥30 mg, to 48 weeks
of double-blind dapagliflozin 5 (n =
141) or 10 mg (n = 140) or placebo
(n = 139) every day plus open-label
pioglitazone
n = 279
48 weeks
At week 24, the mean reduction from baseline in
HbA(1c) was -0.42% for placebo versus -0.82 and -
0.97% for dapagliflozin 5 and 10 mg groups,
respectively (P = 0.0007 and P < 0.0001 versus
placebo).
Patients receiving pioglitazone alone had greater weight
gain (3 kg) than those receiving dapagliflozin plus
pioglitazone (0.7-1.4 kg) at week 48.
In patients with type 2 diabetes
inadequately controlled on pioglitazone,
the addition of dapagliflozin further
reduced HbA(1c) levels and mitigated the
pioglitazone-related weight gain without
increasing hypoglycemia risk.
Title: Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk
in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy
Ref: Diabetes Care 2012 Jul;35(7):1473-8
Key massage: Addition of Dapa to Pio reduced HbA(1c) levels and mitigated the pioglitazone-related weight gain
without increasing hypoglycemia risk

31. Inadequately controlled on insulin
≥30 IU/day, with or without up to
two oral antidiabetic drugs
Placebo or 2.5, 5 or 10 mg/day of
dapagliflozin for 104 weeks.
n = 808
104 weeks
Mean HbA1c changes from baseline at 104 weeks were
-0.4% in the placebo group and -0.6 to -0.8% in the
dapagliflozin groups. In the placebo group, mean insulin
dose increased by 18.3 IU/day and weight increased by
1.8 kg at 104 weeks, whereas in the dapagliflozin
groups, insulin dose was stable, and weight decreased
by 0.9-1.4 kg
Dapagliflozin improved glycaemic control, stabilized
insulin dosing and reduced weight without increasing
major hypoglycaemic episodes over 104 weeks in
patients whose T2DM was inadequately controlled on
insulin. However, rates of genital infection and of UTI
were elevated with dapagliflozin therapy.
Title: Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and
safety over 2 years
Ref: Diabetes Obes Metab . 2014 Feb;16(2):124-36..
Key message: Dapa + Insulin improved glycaemic control, stabilized insulin dosing and reduced
weight without increasing major hypoglycaemic episodes

32. Inadequate glycemic control
(HbA1c 8.0-12.0% [64-108
mmol/mol]) despite stable
metformin monotherapy (≥1,500
mg/day)
Exenatide 2 mg QW plus once-daily
dapagliflozin 10 mg, exenatide QW
plus placebo, or dapagliflozin plus
placebo.
n = 695 patients
104-week
he adjusted least squares mean change (SE) from
baseline to week 104 in HbA1c was greater with exenatide
QW plus dapagliflozin (-1.70% [0.11]) versus exenatide
QW plus placebo (-1.29% [0.12]; P = 0.007) and
dapagliflozin plus placebo (-1.06% [0.12]; P < 0.001).
Clinically relevant changes in FPG, 2-h PPG, weight, and
SBP were also observed with exenatide QW plus
dapagliflozin
In this exploratory analysis, among those individuals
who completed the trial without rescue therapy, there
was clinically relevant efficacy over 2 years with
exenatide QW plus dapagliflozin, with no unexpected
safety findings.
Title: Efficacy and Safety Over 2 Years of Exenatide Plus Dapagliflozin in the DURATION-8 Study:
A Multicenter, Double-Blind, Phase 3, Randomized Controlled Trial
Ref: Diabetes Care 2020 Oct;43(10):2528-2536
Key massage: 2 years with exenatide QW plus dapagliflozin, with no unexpected safety findings.

33. Adult patients with type 2 diabetes
mellitus (T2DM)
Dapagliflozin combined with
conventional antidiabetic drugs
12 RCTs
NA
HbA1c calculated from mean difference was -0.52% (Z=-13.56,
p<0.001) with 95% CI (-0.60 to -0.45). The effect size of FPG was
-1.13 mmol/L (Z=-11.12, p<0.001) with 95% CI (-1.33 to -0.93).
The effect size of body weight was -2.10 kg (Z=-18.77, p<0.001)
with 95% CI (-2.32 to -1.88).
The meta-analysis showed that dapagliflozin as an
add-on drug to conventional antidiabetic drugs
improved the glycaemic control in T2DM participants
without significant body weight gain.
Title: The efficacy of dapagliflozin combined with hypoglycaemic drugs in treating type 2 diabetes
mellitus: meta-analysis of randomised controlled trials
Ref: BMJ Open . 2014 Apr 7;4(4):e004619
Key message: Dapagliflozin as an add-on drug to conventional antidiabetic drugs improved the
glycaemic control in T2DM participants without significant body weight gain

34. PK
34
Bioavailability 78% (after 10 mg dose)
Protein binding ~91%
Metabolism UGT1A9 (major), CYP (minor)
Metabolites Dapagliflozin 3-O-glucuronide (inactive)
Elimination half-life ~12.9 hours
Excretion Urine (75%), feces (21%)
US FDA approved information

35. 35
Indication Recommended dose Additional information
In patients with CKD at risk of progression, to
reduce the risk of sustained eGFR decline,
ESKD, CV death, and hospitalization for heart
failure
10 mg Not recommended for initiation of treatment in
eGFR <25 mL/min/1.73 m2
Not recommended in dialysis
In patients with HFrEF, to reduce the risk of CV
death and hospitalization for heart failure
10 mg Not recommended for initiation of treatment in
eGFR <25 mL/min/1.73 m2
Not recommended in dialysis
In patients with T2D and either multiple CV risk
factors or eCVD, to reduce the risk
of hospitalization for heart failure
10 mg Not recommended for initiation of treatment in
eGFR <25 mL/min/1.73 m2
Not recommended in dialysis
In patients with T2D, for glycemic control 5-10 mg Not recommended for use to improve glycemic
control in adults with type 2 diabetes mellitus
with an eGFR less than 45 mL/min/1.73 m2. It is
likely to be ineffective in this setting based upon
its mechanism of action.
eGFR less than 25: Initiation is not recommended; however, patients may continue 10 mg orally once daily to reduce the risk of eGFR
decline, ESKD, CV death and hHF
US FDA approved information

36. Dosage and administration
36
eGFR (mL/min/1.73 m²) Recommended Dose
eGFR 45 or greater
To improve glycemic control, the recommended starting dose is 5 mg orally once
daily. Dose can be increased to 10 mg orally once daily for additional glycemic
control*.
For all other indications, the recommended starting dose is 10 mg orally once
daily.
eGFR 25 to less than 45 10 mg orally once daily*.
eGFR less than 25
Initiation is not recommended; however, patients may continue 10 mg orally
once daily to reduce the risk of eGFR decline, ESKD, CV death and hHF.
On dialysis Contraindicated.
* not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR
less than 45 mL/min/1.73 m². It is likely to be ineffective in this setting based upon its mechanism of action.
hHF: hospitalization for heart failure, CV: Cardiovascular, ESKD: End Stage Kidney Disease.
US FDA approved information

37. In Patients With
HFrEF With &
Without T2D
1.Maddox TM, Januzzi JL Jr, Allen LA, et al; Writing Committee. 2021 Update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment:
answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll
Cardiol. 2021;77(6):772-810.
2.McDonagh TA, Metra M, Adamo M, et al; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur

38. 38

39. 39

40. Type 2 diabetes who had or were at
risk for atherosclerotic
cardiovascular disease
Dapagliflozin or placebo
17,160 patients
. 4.2 years
Lower rate of cardiovascular death or hospitalization for heart
failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95;
P=0.005), which reflected a lower rate of hospitalization for heart
failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88)
In patients with type 2 diabetes who had or were at
risk for atherosclerotic cardiovascular disease,
treatment with dapagliflozin did not result in a higher
or lower rate of MACE than placebo but did result in a
lower rate of cardiovascular death or hospitalization
for heart failure, a finding that reflects a lower rate of
hospitalization for heart failure
Title: Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes: DECLARE–TIMI 58
Ref: N Engl J Med 2019; 380:347-357
Key message: Dapagliflozin lowers rate of cardiovascular death or hospitalization for heart failure, a
finding that reflects a lower rate of hospitalization for heart failure

41. Patients with HF
Dapagliflozin or placebo
6738 patients
. NA
Patients receiving dapagliflozin showed a significantly
lower incidence of HHF [risk ratio (RR) 0.72; P <
0.00001], all-cause mortality (RR 0.83; P = 0.004),
cardiovascular death (RR 0.86; P = 0.03), and MACE
(RR 0.88; P = 0.03). Moreover, patients receiving
dapagliflozin also showed significant improvements in
systolic blood pressure and body weight
This meta-analysis suggests that
dapagliflozin could be a therapeutic
strategy for patients with HF regardless of
the presence or absence of T2DM.
Title: Effects of Dapagliflozin on Cardiovascular Events, Death, and Safety Outcomes in Patients
with Heart Failure: A Meta-Analysis
Ref: Am J Cardiovasc Drugs . 2021 May;21(3):321-330
Key message: Dapagliflozin is effective HF regardless of the presence or absence of T2DM

42. Left ventricular ejection fraction
≤40%, New York Heart Association
(NYHA) class II-III, estimated
glomerular filtration rate ≥30
mL/min/1.73m2, and elevated
natriuretic peptides.
Dapagliflozin 10 mg daily or
placebo for 12 weeks.
263 patients
. 12 week
There was no significant difference in average 6- and 12-week
adjusted NT- proBNP with dapagliflozin
Meaningful improvement in Kansas City Cardiomyopathy
Questionnaire overall summary score or NT- proBNP, 61.5% of
dapagliflozin-treated patients met this end point versus 50.4%
with placebo (adjusted OR 1.8, 95% CI 1.03-3.06,
nominal P=0.039).
Results were consistent among patients with or without type 2
diabetes mellitus, and other prespecified subgroups (all P values
for interaction=NS).
In patients with heart failure and reduced ejection
fraction, use of dapagliflozin over 12 weeks did not
affect mean NT- proBNP but increased the proportion
of patients experiencing clinically meaningful
improvements in HF-related health status or
natriuretic peptides. Benefits of dapagliflozin on
clinically meaningful HF measures appear to extend
to patients without type 2 diabetes mellitus.
Title: Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart
Failure With Reduced Ejection Fraction: The DEFINE-HF Trial
Ref: Circulation 2019 Oct 29;140(18):1463-1476.
Key massage: Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to
patients without type 2 diabetes mellitus.

43. This study was conducted in patients
with type 2 DM and glycohemoglobin
of7.0% to 10.0% accompanied by LV
diastolic dysfunction at least grade 1
(relaxation abnormality) on resting
echocardiography
dapagliflozin 10 mg once daily or
placebo
n = 60
24 weeks
Dapagliflozin to standard antihyperglycemic treatment in
patients with type 2 DM was associated with a
significant improvement in LV diastolic dysfunction
assessed with DSE as compared with placebo. The use
of dapagliflozin also resulted in a significant decrease in
estimated LV filling pressure during exercise in patients
with type 2 DM
Dapagliflozin improved LV diastolic dysfunction to a
greater extent than placebo in patients with type 2
DM.
Title: Randomized, Controlled Trial to Evaluate the Effect of Dapagliflozin on Left Ventricular
Diastolic Function in Patients With Type 2 Diabetes Mellitus: The IDDIA Trial
Ref: Diabetes Care. 2014;37(3):740-50.
Key massage: Dapagliflozin improved LV diastolic dysfunction

44. In Patients With CKD at Risk of
Progression,
With or Without T2D
The first therapy approved in 20 years to help delay the worsening of CKD in patients at
risk of progression, with and without T2D.1
help protect your patients with CKD at risk of progression against worsening kidney
function, ESKD, CV death, and hospitalization for heart failure—so they can live life.1
complements ACEI/ARB therapy to help provide additional kidney protection1
provides a novel pathway for the treatment of CKD.1
reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This
may drive a feedback mechanism in the kidney, which decreases intraglomerular pressure
44
1. US FDA approved prescription information
2. Circulation. 1998;97(14):1411-1420
3. Net Rev Nephrol. 2017;13(1):11-26
4. N Engl J Med. 2020;383(15):1436-1446

45. N Engl J Med. 2020;383(15):1436-1446

46. GFR of 25 to 75 ml per minute per 1.73
m2 of body-surface area and a urinary
albumin-to-creatinine ratio of 200 to
5000 (CKD with without diabetes
mellitus)
Dapagliflozin 10 mg once daily or
placebo
n = 4304 participants
Median of 2.4 years
Sustained decline in the estimated GFR of at least 50%(hazard
ratio, 0.61; 95% confidence interval [CI], 0.51 to 0.72; P<0.001;
number needed to treat to prevent one primary outcome event, 19
[95% CI, 15 to 27]).
The hazard ratio for the composite of a sustained decline in the
estimated GFR of at least 50%, end-stage kidney disease, or
death from renal causes was 0.56 (95% CI, 0.45 to 0.68;
P<0.001), and the hazard ratio for the composite of death from
cardiovascular causes or hospitalization for heart failure was 0.71
(95% CI, 0.55 to 0.92; P = 0.009)
Among patients with chronic kidney disease,
regardless of the presence or absence of diabetes,
the risk of a composite of a sustained decline in the
estimated GFR of at least 50%, end-stage kidney
disease, or death from renal or cardiovascular causes
was significantly lower with dapagliflozin than with
placebo.
Title: Dapagliflozin in Patients with Chronic Kidney Disease: DAPA-CKD Trial
Ref: N Engl J Med 2020 Oct 8;383(15):1436-1446.
Key massage: Reduced risk of decline in CKD

47. 47

48. Precautions
Ketoacidosis
• Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level.
• Temporary discontinuation in situations known to predispose to ketoacidosis
Volume Depletion:
• manifest as symptomatic hypotension or acute transient changes in creatinine.
• Acute kidney injury
• Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for
volume depletion or hypotension.
Urosepsis and Pyelonephritis
Hypoglycemia
• risk of hypoglycemia when co-administered with insulin and insulin secretagogues
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
• Rare but serious,
• Assess patients presenting with pain or tenderness, erythema, swelling in the genital or perineal area, along with fever or malaise.
Genital Mycotic Infections:
• particularly in patients with prior genital mycotic infections. Monitor and treat appropriately
48

49. 49

50. Contraindications
• Prior serious hypersensitivity
• Patients on dialysis
50

51. Adverse reactions
In a pool of 12 placebo-controlled studies,
the most common adverse reactions (≥5%)
associated with Dapa 5 mg, 10 mg, and
placebo respectively were female genital
mycotic infections (8.4% vs 6.9% vs 1.5%),
nasopharyngitis (6.6% vs 6.3% vs
6.2%), and urinary tract infections (5.7% vs
4.3% vs 3.7%).
51

52. Use in
Specific
Populations
52
• Not recommended during the second and third trimesters of pregnancy.
Pregnancy
• not recommended when breastfeeding
Lactation
• Safety and effectiveness in pediatric patients under 18 years of age have not
been established.
Pediatric Use
• No dosage change is recommended based on age.
Geriatric Use
• contraindicated in patients on dialysis
• Not recommended for use to improve glycemic control in adults with type 2
diabetes mellitus with an eGFR less than 45 mL/min/1.73 m2. It is likely to
be ineffective in this setting based upon its mechanism of action. eGFR less
than 25 Initiation is not recommended, however patients may continue 10
mg orally once daily to reduce the risk of eGFR decline, ESKD, CV death
and hHF.
Renal Impairment
• No dose adjustment is recommended for patients with mild, moderate, or
severe hepatic impairment.
Hepatic Impairment

53. 53
Types of SGLT2 inhibitors
Indications (US FDA)
Name of drug
Regulatory
approvals
Type 2 diabetes
Type-2 diabetes
with CVD
Tyep-2 diabetes
with CKD / Diabetic
nephropathy
HFrEF
Canagliflozin
EU-2013
US FDA-2013
India : 2014
Yes Yes Yes No
Dapagliflozin
EU-2012
USFDA-2014
India : 2015
Yes Yes Yes
Yes ( ESC & ACC
recommends ,US
FDA approved
indication)
Empagliflozin
EU-2014
US FDA- 2014
India: 2015
Yes Yes No
Yes (ESC & ACC
recommended , but
not US FDA
approved
indication)
Ertugliflozin
EU-2018
US FDA- 2017
Yes No No No
Ipragliflozin Japan -2014 Yes No No No
Luseogliflozin Japan -2014 Yes No No No
Tofogliflozin Japan-2014 Yes No No No
Remogliflozin
etabonate
India- 2019 Yes No No No
Adopted from US FDA prescription information.

54. Take Home Message
54

55. • Key functions of Insulin is helping organs to utilize the glucose as energy source ,
formation of fat , glycogen and protein
Functions of Insulin
• Diabetes is characterized by hyperglycemia secondary to loss of insulin secreting
Beta cells of pancreas and diminished response to Insulin
Definition of Type 2 Diabetes Mellitus
• According to ADA , HbA1c in prediabetes is 5.6-6.4% and diabetes > 6.5%
Diabetes Mellitus diagnosis
• Lack of insulin leads to the release of free fatty acids from adipose tissue (lipolysis)
• Lipid are converted into ketone bodies by Liver
• Ketone causes acidic blood PH (Keto acidosis)
Diabetic Ketoacidosis

56. • ADA: <7%
• AACE: ≤ 6.5%
• ACP : 7-8 %
Treatment goals (Targeted HbA1c)
• First line : Metformin + Diet + Exercises + Lifestyle changes
• Second line if CVD or CKD or HF : GLP-1RA Either/ Or SGLT2i (if GFR is
adequate) _ Still higher HbA1c_ add : DPP4i (If not on GLP-1RA) or Basal Insulin
or SU or TZD
• Second line : No CVD or CKD , Indication to reduce risk of Hypoglycemia _
DPP4i , SGLT2i , GLP-1RA , TZD _ Still higher HbA1c , add drug from DPP4i ,
SGLT2i , GLP-1RA , TZD _ Still higher HbA1c _ add SU or Basal insulin
• Second line : Need to minimize the weight gain or promote the weigh loss _ GLP-
1RA Either/ Or SGLT2i _ Still higher HbA1c add drug from SGLT2i , GLP-1RA
• Second line : Cost is major issue_ SU or TZD _ Still HbA1c high _ add drug from
SU or TZD _ Still hbA1c high _ add Basal insulin or DPP4i or SGLT2i
ADA guidelines

57. • 4 times more often for HF than non-diabetic patients
• Diabetic nephropathy : affects ∼40% of type 1 and type 2 diabetic patients
• 2-4 times higher risk of CVD
• Lack of cardioprotective and renoprotective action of currently available anti diabetic therapies
Need of SGLT2i
• In PCT , glucose is reabsorbed by Sodium-Glucose Cotransporters 2
• SGLT2i , inhibit SGLT2 channels , thereby causing glucose and sodium excretion in the urine ,
which leads to
• Glucosuria
• Natriuresis
• Diuresis
• Clinical benefits
• Reduced blood sugar
• Reduced blood pressure
• Reduced intraglomerular pressure
• Increased lipolysis
• Reduction in weight
• Euglycemic ketosis
SGLT2i MOA

58. Dapagliflozin
MOA
• Inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2) which are responsible for at least 90% of the glucose reabsorption
in the kidney
PK
• T1/2: 12.9 hours
• Excretion: Urine (75%), feces (21%)
Indications , Dosage and Administration
• T2DM : 5-10 mg OD
• T2DM with risk or established CVD to reduce HF related hospitalization : 10 mg OD
• HFrEF : 10 mg OD
• CKD : 10 mg OD
• With or without food
Limitations for uses
• eGFR less than 25: Initiation is not recommended; however, patients may continue 10 mg orally once daily to reduce the risk of eGFR
decline, ESKD, CV death and hHF
• Not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73
m2
Contraindications
• Dialysis

59. Dapagliflozin T2DM
• Monotherapy
• Reduces HbA1c by - 0.65 % vs
Placebo
• Initial Dapa + Metformin
• Reduces HbA1c by - 1.98 to – 2.05
% vs monotherapies
• Reduced weight by -2.66 to -3.33 kg
• Inadequate Metformin response
• Reduces HbA1c by – 0.70% to -
0.84%
• Vs glipizide
• Comparable HbA1c reduction by –
0.52%
• Inadequate glycaemic control with
glimepiride
• Reduces HbA1c by -0.63, -0.82%
• Reduced weight and safe
T2DM
• Inadequate control by
metformin and glimepiride
• Reduces HbA1c by -
0.69%
• Inadequately controlled on
pioglitazone monotherapy
• Reduces HbA1c by -0.82
and -0.97%
• Receiving high doses of
insulin
• Reduces HbA1c by -0.6 to
-0.8%
• With insulin
• Reduces HbA1c by –
1.70%

60. Dapagliflozin
Guidelines
• ACC & ESC
• Recommended as a component of first-line HFrEF
therapy according to both the 2021 ACC Expert
Consensus Decision Pathway and the 2021 ESC
HF Guidelines.
• ADA
• For patients with established ASCVD or indicators
of high ASCVD risk (such as patients ≥55 years of
age with coronary, carotid, or lower-extremity
artery stenosis >50% or left ventricular
hypertrophy), heart failure, or CKD, an SGLT2
inhibitor or GLP-1 RA with demonstrated CVD
benefit
• Second line : No CVD or CKD , Indication to
reduce risk of Hypoglycemia
• Second line : Need to minimize the weight gain or
promote the weigh loss

61. CVD trials
• DAPA-HF Trial
• Patients with heart failure and a reduced ejection fraction, the risk of worsening heart
failure or death from cardiovascular causes was lower among those who received
dapagliflozin (36% risk reduction )
• DECLARE–TIMI 58
• In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular
disease
• Result in a lower rate (13%) of cardiovascular death or hospitalization for heart failure
• Less risk of (24%) renal composite (≥40% decrease in estimated glomerular filtration rate
to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or
death from renal or cardiovascular causes
• DEFINE-HF Trial
• Experiencing clinically meaningful improvements in HF-related health status or natriuretic
peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend
to patients without type 2 diabetes mellitus
• IDDIA Trial
• Dapagliflozin improved LV diastolic dysfunction to a greater extent than placebo in patients
with type 2 DM.

62. CKD trials
• DAPA-CKD Trial
• Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the
risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney
disease, or death from renal or cardiovascular (39% risk reduction) causes was significantly lower
with dapagliflozin
HFrEF
• Dapagliflozin :ESC & ACC recommends ,US FDA approved indication
• Empagliflozin : ESC & ACC recommended , but not US FDA approved indication
Adverse events
• Genital infections (9%)
• 3.52 times vs placebo
• UTI (6%)
• 1.75 times vs placebo
• Ketoacidosis
• Volume deficiencies
• Urosepsis and Pyelonephritis
• Hypoglycemia
• Necrotizing Fasciitis of the Perineum

63. Precautions
• Pregnancy : not recommended in 2nd & 3rd trimester
Renal impairment
• Contraindicated in patients on dialysis
• Not recommended for use to improve glycemic control in adults with type 2
diabetes mellitus with an eGFR less than 45 mL/min/1.73 m2. It is likely to
be ineffective in this setting based upon its mechanism of action
• eGFR less than 25 Initiation is not recommended, however patients may
continue 10 mg orally once daily to reduce the risk of eGFR decline, ESKD,
CV death and hHF
Hepatic Impairment
• No dose adjustment is recommended for patients with mild, moderate, or
severe hepatic impairment.