dapagliflozin

1. Josef von Mering (1849-1908)
Josef von Mering discovered the glucosuric effect of phlorizin in
1888.
History
Phlorizin came from the root bark of
the apple tree
in 1995, NIDDK-funded researchers found that phlorizin
inhibited both SGLT1 and SGLT2

2. The role of Kidney in Glucose Homeostasis
This Photo by Unknown Author is licensed under CC BY-SA-NC
gluconeogenesis
glucose filtration
glucose
consumption
glucose
reabsorption
responsible for up to 20% of all
glucose production via
gluconeogenesis

3. Renal Actions of SGLT2 inhibitors.
De Fronzo et al 2009

4. Current SGLT2 inhibitors Approved by FDA
• Canagliflozin
• Empagliflozin
• Dapagliflozin
• Ertugliflozin

5. SGLT2 inhibitors play a role in the following
settings ( Type 2 DM):
• Overt atherosclerotic (CVD) not reaching glycaemic goals with metformin and lifestyle
modifications (empagliflozin, canagliflozin, and dapagliflozin, but not ertugliflozin).
• Heart failure not reaching glycaemic goals with metformin and lifestyle modifications
(empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin).
• As a third-line agent in patients not meeting glycemic goals on two oral agents.
• As a second agent in patients with inadequate glycemic control on metformin who are
unwilling or unable to consider injection therapy and in whom weight gain and risk of
hypoglycemia are a significant issue

6. Heart Failure in non diabetic: As a Secondary
pharmacologic therapy
• Heart failure with reduced ejection fraction (HFrEF) ejection fraction ≤
40%
• NYHA classes II–IV
• Elevated NT-proBNP
• All ejection fractions
• Dapagliflozin is 10 mg once daily.
• Empagliflozin is 10 mg once daily

7. CKD (with or without diabetes)
As an Additional therapies in proteinuric patients
• Diabetic kidney disease: T2DM
• Aetiology of kidney disease: ischemic nephropathy, IgA nephropathy,
FSGS, chronic pyelonephritis, chronic interstitial nephritis
• No immunosuppression in the prior 6 months
• ONLY Dapagliflozin 10 mg for diabetic and non-diabetic ( DAPA CKD)
• Canagliflozin for Diabetic kidney disease only (CREDENCE Study)
• Empagliflozin not yet approved (EMPA-KIDNEY result is pending)

8. SGLT2 inhibitors and eGFR
Glycaemic control
• eGFR ≥60 ml/min per 1.73 m2 anticipated HbA1c ↓: 0.6%–0.9%
• eGFR 45–59 ml/min per 1.73 m2 anticipated HbA1c ↓: 0.3%–0.5%
• eGFR < 45 ml/min per 1.73m2 Anticipated HbA1c ↓: minimal
SGLT2 inhibitors have less glycaemic benefit in patients with more severe
kidney disease at initiation, and for the specific treatment of hyperglycemia,
SGLT2 inhibitors are not recommended for initiation in patients with eGFR <30
mL/min/1.73 m2 (empagliflozin, canagliflozin), <45 mL/min/1.73 m2
(dapagliflozin, ertugliflozin)

9. SGLT2 inhibitors and eGFR
• Diabetic kidney disease & Nondiabetic kidney disease
• eGFR ≥ 25 ml/min per 1.73 m2
• UACR 200–5000 mg/g
• Congestive heart failure
• eGFR >20 ml/min per 1.73 m2

10. Practical Point: Accepting the Acute “Dip” in eGFR
• SGLT2 inhibitors are well recognized to result in an acute transient
reduction in GFR
• larger magnitude of dip in eGFR correlates with greater long-term
benefit and therefore should be viewed as evidence of a positive
hemodynamic effect
• Monitor kidney function 1 month after initiation in higher risk
patients, including those with a history of prior acute kidney injury,
advanced CKD, or in those in whom there is increased concern
regarding volume depletion
increase in serum creatinine level by up to 30%
from baseline is considered acceptable.

11. Contraindications
and precautions

12. • Type 1 diabetes
• Presence of type 2 DM with prior DKA or a condition predisposing to
DKA (including pancreatic insufficiency, drug or alcohol addiction)
• Type 2 diabetes and eGFR <45 mL/min/1.73 m2 (dapagliflozin,
ertugliflozin), or <30 mL/min/1.73 m2 (empagliflozin, canagliflozin)
• For HF, eGFR <30 ml per minute per 1.73 m2 (except for
empagliflozin, for which the threshold is <20 ml per minute per 1.73
m2), end-stage kidney disease, or rapidly declining renal function.

13. Avoid use of SGLT2 inhibitors in patients with
• Frequent bacterial urinary tract infections or genitourinary yeast
infections.
• Low bone mineral density and high risk for fracture and falls
• Foot ulceration (eg, neuropathy, foot deformity, vascular disease,
and/or history of previous foot ulceration)
• Ketogenic diet

14. Before Starting SGLT2 inhibitors
Educate patients on the symptoms and
risks of DKA and appropriate steps to
take if symptoms or signs occur,
including discontinuing SGLT2 inhibitor
and seeking immediate medical
attention.
Temporary discontinuation of SGLT2
inhibitor and monitoring for
ketoacidosis are recommended in
situations known to predispose to
ketoacidosis (such as prolonged fasting
due to illness or perioperative state).
SGLT2 inhibitors need to stop at least 3 days preoperatively

15. Cardiovascular
Effects

16. Salvatore et al. An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors.
Int. J. Mol. Sci. 2022, 23, 3651.

17. Atherosclerotic Cardiovascular Disease
(CVD)
Empagliflozin and canagliflozin have
been shown to decrease
atherosclerotic cardiovascular
morbidity and mortality in patients
with T2DM and overt CVD. (CANVAS
and EMPA-REG trials)
In the primary analysis, dapagliflozin
did not appear to reduce
atherosclerotic cardiovascular
morbidity or cardiovascular
mortality. however, it decreased
cardiovascular outcomes in a
subanalysis of the primary trial.

18. Heart Failure
In patients with type 2 diabetes and heart failure, all SGLT2 inhibitors
have shown salutary effects.
Kanie T ETAL. Dipeptidyl peptidase‐4 inhibitors, glucagon‐like peptide 1 receptor agonists and sodium‐glucose co‐transporter‐2 inhibitors for
people with cardiovascular disease: a network meta‐analysis. Cochrane Database of Systematic Reviews 2021, Issue 10. Art. No.: CD013650.
DOI: 10.1002/14651858.CD013650.pub2. Accessed 18 September 2022.

19. Until large, prospective, randomized trials are conducted, it is
unknown whether SGLT2 inhibitors will have similar CVD effects
in the majority of persons with type 2 diabetes who do not have
overt CVD

20. Dapagliflozin and Cardiovascular Outcomes in Type
2 Diabetes (DECLARE-TIMI 58 )
major adverse cardiovascular events (MACE), defined as
cardiovascular death, myocardial infarction, or ischemic stroke
17,160 patients with type 2
diabetes (mean A1C
approximately 8.3 percent)
who had or were at risk for
CVD

21. 3 wishes
a Diabetologist met a genie and claimed his three wishes
Genie : you can ask for anything other than love or money .
Diabetologist : why ? Do you have specialties ?
Genie : yes and my subspecialty is profession , for example my former master was
karim Benzema ( with sneaky smile )
Diabetologist : ok then , my first wish is as follow “ I want an oral hypoglycemic
agent that control blood glucose level but don’t cause hypoglecemia “
Genie: done

22. 2nd and third wishes
Diabetologist : Second wish “ it can be used as a first line or added to the most widely used
drugs or insulin “
Genie : done
Diabetologist : third wish “ it must have a huge cardiovascular benefits and minimal side
effects with ”
Genie : done , may I present to you the SGLT2 inhibitor , dapagliflozin .
Let me explain :
1st : it can be used alone

23. 2
Ferrannini E, Ramos SJJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic
patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-
controlled, phase 3 trial. Diabetes Care,. 2010; 33 (10); 2217-24.
•
A 24-week parallel-group, double-blind,
placebo-controlled phase 3 trial.
•
Patients with A1C 7.0–10 were randomly
assigned to receive once-daily placebo or
2.5, 5, or 10 mg dapagliflozin once daily in
the morning
•
The reductions in A1C were statistically
significant with 5 and 10 mg dapagliflozin.
Dapagliflozin monotherapy in treatment-naïve type 2 diabetic patients with
inadequate glycemic control by diet and exercise

24. 3
Ferrannini E, Ramos SJJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2
diabetic patients with inadequate glycemic control by diet and exercise: a randomized,
double-blind, placebo-controlled, phase 3 trial. Diabetes Care,. 2010; 33 (10); 2217-24.
Reductions in FPG were apparent as
early as week 1. Throughout the study,
FPG reductions were more marked in
5 and 10 mg dapagliflozin arms and
were statistically significant at week 24
Dapagliflozin monotherapy in treatment-naïve type 2 diabetic patients with
inadequate glycemic control by diet and exercise

25. 4
Ferrannini E, Ramos SJJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients
with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled,
phase 3 trial. Diabetes Care,. 2010; 33 (10); 2217-24.
Body weight decreases were greater
with all dapagliflozin doses than with
placebo
Dapagliflozin monotherapy in treatment-naïve type 2 diabetic patients with
inadequate glycemic control by diet and exercise

26. 5
Ji L, Ma J, Li H, Mansfield TA, T'joen CL, Iqbal N. Dapagliflozin as Monotherapy in Drug Naïve Asian Patients With Type2 Diabetes Mellitus: A
Randomized, Blinded, Prospective Phase III Study . Clinical Therapeutics. 2014; 36 (1); 84-100
•
Phase III, multicenter, parallel group,
double-blind study
•
Drug-naive patients with HbA1c levels
7.0%-10.5% were randomized to
receive placebo, dapagliflozin (DAPA)
5 mg, or dapagliflozin 10 mg
•
Compared with placebo, dapagliflozin
5 and 10 mg demonstrated clinically
and statistically significant
improvements in HbA1c levels after 24
weeks of treatment
Dapagliflozin as monotherapy in drug-naive Asian patients with type 2
diabetes whose disease was inadequately controlled with diet and exercise.

27. 6
Ji L, Ma J, Li H, Mansfield TA, T'joen CL, Iqbal N. Dapagliflozin as Monotherapy in Drug Naïve Asian Patients With Type2 Diabetes Mellitus: A
Randomized, Blinded, Prospective Phase III Study . Clinical Therapeutics. 2014; 36 (1); 84-100
Dose-dependent, statistically significant
reductions in fasting plasma glucose were
observed for both doses (5 mg and 10 mg)
compared with placebo
Dapagliflozin as monotherapy in drug-naive Asian patients with type 2
diabetes whose disease was inadequately controlled with diet and exercise.

28. 7
Ji L, Ma J, Li H, Mansfield TA, T'joen CL, Iqbal N. Dapagliflozin as Monotherapy in Drug Naïve Asian Patients With Type2
Diabetes Mellitus: A Randomized, Blinded, Prospective Phase III Study . Clinical Therapeutics. 2014; 36 (1); 84-100
Dapagliflozin also resulted in significant reductions
from baseline in total weight compared with
placebo
Dapagliflozin as monotherapy in drug-naive Asian patients with type 2
diabetes whose disease was inadequately controlled with diet and exercise.

29. Genie : it can be used with insulin or other drugs .
First : insulin

30. 8
Wilding JP, Woo V, Rohwedder K, Sugg J, Parikh S. Dapagliflozin in patients with type 2 diabetes
receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab. 2014
•
A 24‐week, randomized, placebo‐controlled,
double‐blinded, multicenter trial
•
Patients, whose T2DM was inadequately
controlled on insulin ≥30 IU/day, with or without
up to two oral antidiabetic drugs, were
randomly assigned to receive placebo or 2.5, 5
or 1
0
mg/day of dapagliflozin for 104weeks
•
Dapagliflozin stabilized glycemic control to a
mean level close to 7.5% in a difficult‐to‐treat
population of older patients (mean age 59.3)
with T2DM of long duration (mean age 13.6)
and substantial diabetes‐related and
cardiovascular comorbidity
Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin

31. 9
Wilding JP, Woo V, Rohwedder K, Sugg J, Parikh S. Dapagliflozin in patients with type 2
diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes
Metab. 2014
Glycaemic control was achieved without an
increase in mean daily insulin requirement for the
dapagliflozin‐treated patients over a 104‐week
period.
Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin

32. 10
Wilding JP, Woo V, Rohwedder K, Sugg J, Parikh S. Dapagliflozin in patients with type 2
diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes
Metab. 2014
Reductions in total body weight in the dapagliflozin
groups by 4
8
weeks were maintained over 104weeks
Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin

33. Genie:
It can be combined with other drugs

34. 11
Nauck MA, Del Prato S, Meier JJ, Durán-García S, Rohwedder K, Elze M. Dapaglif lozin Versus
Glipizide as Add-on Therapy in Patients With Type 2 Diabetes Who Have Inadequate Glycemic
Control With Metformin. Diabetes Care. 2011; 34 (9): 2015-2022
•
52-week, double-blind, multicenter, active-
controlled, noninferiority trial randomized
patients with type 2 diabetes (baseline
mean HbA1c, 7.7%), who were receiving
metformin monotherapy, to add-on
dapagliflozin or glipizide
•
Although the initial drop in HbA1c during
the titration period with glipizide was
greater than that observed with
dapagliflozin, efficacy for glipizide
declined during the maintenance period
but remained stable for dapagliflozin. This
resulted in equivalent efficacy at week 52
Dapagliflozin versus glipizide as add-on therapy in patients with type 2
diabetes who have inadequate glycemic control with metformin

35. 12
Nauck MA, Del Prato S, Meier JJ, Durán-García S, Rohwedder K, Elze M. Dapaglif lozin Versus
Glipizide as Add-on Therapy in Patients With Type 2 Diabetes Who Have Inadequate Glycemic
Control With Metformin. Diabetes Care. 2011; 34 (9): 2015-2022
Whereas glipizide treatment led to
weight gain and more hypoglycemic
episodes, dapagliflozin produced
significant weight loss and significantly
fewer hypoglycemic episodes
Dapagliflozin versus glipizide as add-on therapy in patients with type 2
diabetes who have inadequate glycemic control with metformin

36. 13
Matthaei S, Bowering K, Rohwedder K, Grohl A, Parikh S. Dapagliflozin Improves Glycemic Control and
Reduces Body Weight as Add-on Therapy to Metformin Plus Sulfonylurea: A 24-Week Randomized,
Double-Blind Clinical Trial. Diabetes Care. 2015; 38(3):365–372
•
A 24-Week Randomized, Double-Blind
Clinical Trial. Patients with HbA1c of
7.0% to 10.5% receiving sulfonylurea and
metformin were randomized to receive
dapagliflozin 10 mg/day or placebo
•
HbA1c levels were significantly reduced
from baseline over 24 weeks in patients
treated with dapagliflozin compared with
placebo
Dapagliflozin as add-on therapy to
Metformin Plus Sulfonylurea

Dapagliflozin in triple therapy in combination with metformin
plus sulfonylurea is not recommended according to NICE
guidelines.

Please refer to the local SPC for licensed indications

37. 14
Matthaei S, Bowering K, Rohwedder K, Grohl A, Parikh S. Dapagliflozin Improves Glycemic Control and Reduces
Body Weight as Add-on Therapy to Metformin Plus Sulfonylurea: A 24-Week Randomized, Double-Blind Clinical
Trial. Diabetes Care. 2015; 38(3):365–372
Greater reductions from baseline to week 24
in FPG were observed with dapagliflozin
compared with placebo
Dapagliflozin as add-on therapy to Metformin Plus Sulfonylurea

38. 15
Matthaei S, Bowering K, Rohwedder K, Grohl A, Parikh S. Dapagliflozin Improves Glycemic Control and Reduces
Body Weight as Add-on Therapy to Metformin Plus Sulfonylurea: A 24-Week Randomized, Double-Blind Clinical Trial.
Diabetes Care. 2015; 38(3):365–372
Significantly greater reductions from
baseline to week 24 in body weight were
observed with dapagliflozin compared with
placebo.
Dapagliflozin as add-on therapy to Metformin Plus Sulfonylurea

39. 16
Rosenstock J, Hansen L, Zee P, Li Y, Cook W, Hirshberg B. Dual Add-on Therapy in Type 2 Diabetes Poorly Controlled With
Metformin Monotherapy: A Randomized Double-Blind Trial of Saxagliptin Plus Dapagliflozin Addition Versus Single Addition of
Saxagliptin or Dapaglif lozin to Metformin. Diabetes Care. 2015; 38(3):376-83
•
A double-blind trial in adults with HbA1c
≥8.0% and ≤12.0%, randomized to
saxagliptin (SAXA) (5 mg/day) plus
dapagliflozin (DAPA) (10 mg/day), or SAXA
(5 mg/day) and placebo, or DAPA (10
mg/day) and placebo on background
metformin extended release (MET) ≥1,500
mg/day
•
The addition of SAXA+DAPA to MET
therapy resulted in significantly greater
reductions from baseline in HbA1c at 24
weeks than did therapy with SAXA+MET or
DAPA+MET
Saxagliptin plus dapagliflozin versus saxagliptin and dapagliflozin added on
alone in patients with type 2 diabetes poorly controlled with metformin

40. Genie : lastly , cardiovascular and other beneficial effects and minimal side effects

41. 17
Sonesson C, Johanasson PA, Johnsson E, Gause-Nilsson I. Cardiovascular effects
of dapagliflozin in patients with type 2 diabetesand different risk categories: a meta-analysis. Cardivasc
Diabetol. 2016
A pre-specified meta-analysis of cardiovascular
(CV) events from 21 phase 2b/3 dapagliflozin
clinical trials was undertaken to characterize
the CV profile of dapagliflozin
Patients with type 2 diabetes, both overall and
with different levels of CV risk, including CV
disease (CVD) history, age and other CV risk
factors, were analyzed
The results suggest the potential for a
beneficial CV effect by dapagliflozin which is
consistent with the multifactorial benefits on CV
risk factors associated with SGLT2 inhibitors.
Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and
different risk categories

42. 18

43. 19
Objective:
To compare dapagliflozin with DPP-4 inhibitors with regard to risk
associations with major adverse cardiovascular (CV) events (MACE; non-
fatal myocardial infarction, non-fatal stroke or cardiovascular mortality),
hospitalization for heart failure (HHF), atrial fibrillation and severe
hypoglycaemia in patients with type 2 diabetes (T2D) in a real-world
setting.

44. A total of 40 908 patients with T2D were identified
10,227 new users of dapagliflozin
30,681 DPP-4 inhibitor
Hikma Pharmaceuticals PLC 20
Methods:
All patients with T2D prescribed glucose-lowering drugs during
2012 to 2015 were identified in nationwide registries in
Denmark, Norway and Sweden.
Patients were divided into two groups: new users of
dapagliflozin and new users of DPP-4 inhibitors

45. 21

46. 22
Dapagliflozin was associated with a lower risk of MACE, HHF and all-cause
mortality compared with DPP-4 inhibitors.
Dapagliflozin was associated with lower risks of CV events and all-cause mortality
compared with DPP-4 inhibitors in a real-world clinical setting and a broad T2D
population.
Results

47. 23
Observational effectiveness studies cannot replace randomized clinical
trials, but might prove to be an important complement to a broader and
more generalized patient population in a real-world setting.
While awaiting more complete evidence, observational comparative
effectiveness studies may increase the understanding of the SGLT-2
inhibitor treatment outcome effects; however, confounding, particularly by
indication, cannot be fully excluded in observational studies, and the large
ongoing prospective trial DECLARE-TIMI 58, including >17 000 patients
with both low and high CV risk, will further elucidate dapagliflozin-specific
findings.

48. Triple antihyperglycemic therapy using a combination of a DPP-4 inhibitor and an SGLT2 inhibitor as dual
add-on to metformin is an effective and well tolerated novel intervention that has not been previously
reported in uncontrolled type 2 diabetes
Hikma Pharmaceuticals PLC
Insert > Header & Footer to change this text 24
Dapagliflozin lowered hyperglycemia in treatment-naive patients with newly diagnosed type 2 diabetes .
Dapagliflozin as monotherapy in drug-naiveAsian patients significantly improved glycemic control with the
additional benefit of weight loss with low rates of hypoglycemia and no increase in renal events. Genital
infections and UTIs were more common with dapagliflozin.
Dapagliflozin improved glycemic control, stabilized insulin dosing and reduced weight without increasing
major hypoglycemic episodes in patients whose T2DM was inadequately controlled on insulin. However,
rates of genital infection and of UTI were elevated with dapagliflozin therapy.
Despite similar glycemic efficacy at the end of the maintenance period, dapagliflozin reduced weight and
produced less hypoglycemia than glipizide in T2DM inadequately controlled with metformin.
Dapagliflozin was well tolerated and effective as add-on to metformin plus sulfonylurea.Adverse effects
included hypoglycemia and genital infections
Conclusion

49. Thank you