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1. Mohammed Abdel Gawad
Nephrology Consultant - Alexandria
MD Nephrology - Mansoura University
drgawad@gmail.com
SGLT2-i, DPP4-i & Incretin Mimetics
Optimizing their use in CKD Patients

2. NephroTube.com
/groups/NephroTube
/NephroTube
/NephroTube

3. To download the lecture contact me
drgawad@gmail.com
For more Nephrology lectures, Monthly Updates,
and Mini-Reviews visit
www.NephroTube.com

4. Nat Rev Nephrol. 2017 Jan;13(1):11-26
Glucagon-like peptide-1 Gastric inhibitory polypeptide
Diabetologia. 2016 May;59(5):907-17
DPP4-i DPP4-i
Incretins
Incretin
mimetic
(GLP-1 RA)

5. Clinical trials of new diabetes drugs
2018 Jan;41(1):14-31

6. Why we are searching for new oral hypoglycemic?
Why the manner in which providers prioritize therapy
options had changed?
Cardiovascular Outcomes
Renal Outcomes

9. SGLT2-i
Incretin
Mimetics
DPP4-i

10. SGLT2-i
DPP4-i
Incretin
Mimetics
• Evidence of superiority or
inferiority?
• Limitations to use?
• Summary & suggested
approach?
Talk Outline

11. SGLT2-i
DPP4-i
Incretin
Mimetics
• Evidence of superiority or
inferiority?
• Limitations to use?
• Summary & suggested
approach?
Talk Outline
?

12. SGLT2-i
DPP4-i
?
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death (vs placebo)
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Incretin
Mimetics
Empagliflozin
Canagliflozin
Dapagliflozin

13. SGLT2-i
DPP4-i
?
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death (vs placebo)
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Incretin
Mimetics
Empagliflozin
Canagliflozin
Dapagliflozin

14. N Engl J Med 2015; 373:2117-2128 N Engl J Med 2017; 377:644-657
Gliflozins significantly decreased risk of composite CV events
Empagliflozin also reduced the risk of CV death
SGLT2-ivsPlacebo

15. N Engl J Med 2015; 373:2117-2128 N Engl J Med 2017; 377:644-657
SGLT2-ivsPlacebo
N Engl J Med 2019;380:347-57
Lower rates of the other primary efficacy outcome which was cardiovascular
death or hospitalization for heart failure
Gliflozins significantly decreased risk of composite CV events
Empagliflozin also reduced the risk of CV death

16. SGLT2-i
DPP4-i
?
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Incretin
Mimetics
Empagliflozin
Canagliflozin
Dapagliflozin

17. SGLT2-ivsDPP4-i
2018 Feb;20(2):344-351

18. SGLT2-i
DPP4-i
?
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Incretin
Mimetics
Empagliflozin
Canagliflozin
Dapagliflozin

19. SGLT2-i
DPP4-i
?
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Incretin
Mimetics
Empagliflozin
Canagliflozin
Dapagliflozin

20. SGLT2-i
DPP4-i
?
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Incretin
Mimetics
Empagliflozin
Canagliflozin
Dapagliflozin

21. SGLT2-i
DPP4-i
?
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Incretin
Mimetics
Empagliflozin
Canagliflozin
Dapagliflozin
13, 11–26 (2017)

22. SGLT2-i
DPP4-i
?
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Incretin
Mimetics
Empagliflozin
Canagliflozin
Dapagliflozin
SGLT2 inhibitors also reverse altered TGF and
direct proximal tubulointerstitial injuryVol. 10 No. 5 September 2019

23. Terminated early
2019 Jun 13;380(24):2295-2306
The risk was lower in the canagliflozin group than in the placebo
group:
• doubling of serum creatinine
• sustained eGFR of <15 ml/min
• time to dialysis or kidney transplantation
• renal or CV mortality
Canagliflozin 100 mg
vs.
Placebo
eGFR 30 to 90 mL/min
UACR 300 to 5000 mg/g

25. September 5, 2019
N Engl J Med 2019;380:347-57
N Engl J Med 2015; 373:2117-2128
N Engl J Med 2017; 377:644-657N Engl J Med 2019 Jun 13;380(24):2295-2306

26. September 5, 2019
SGLT2 reduce dialysis, transplantation,
or death due to kidney disease

27. SGLT2-i
DPP4-i
?
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Incretin
Mimetics
Empagliflozin
Canagliflozin
Dapagliflozin

28. SGLT2-i
DPP4-i
?
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Renal Harm:
Increased risk
of AKI
Incretin
Mimetics
Empagliflozin
Canagliflozin
Dapagliflozin

29. 2016 [cited 2019 Feb 8]

30. Co-morbid factors that could increase this risk:
• CKD
• Reduced blood volume (especially older adults >65 y/o)
• CHF
• When SGLT2-i are co-administered with certain medications:
oDiuretics
oACE-i, ARBS
oNSAIDS
Diabetes Obes Metab. 2015 Mar;17(3):294–303
Consult Pharm. 2014;29(5):335–346

31. September 5, 2019
SGLT2 reduce AKI

32. Incretin
Mimetics
SGLT2-i
DPP4-i
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Renal Harm:
Increased risk
of AKI !

33. Incretin
Mimetics
SGLT2-i
DPP4-i
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Renal Harm:
Increased risk
of AKI !
SGLT2-i for Type 1 DM?
SGLT2-i for Non Diabetic CKD?
SGLT2-i for Non Diabetic HF?

34. Incretin
Mimetics
SGLT2-i
DPP4-i
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Renal Harm:
Increased risk
of AKI
?
!

35. HF/ASCVD/↑CV risk CKD+HF/ASCVD/↑CV risk CKD
Strong evidence Second line ↓ Albuminuria (?)
Incretin
Mimetics
SGLT2-i
DPP4-i
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Renal Harm:
Increased risk
of AKI
?
!

36. HF/ASCVD/↑CV risk CKD+HF/ASCVD/↑CV risk CKD
Strong evidence Second line ↓ Albuminuria (?)
Incretin
Mimetics
SGLT2-i
DPP4-i
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Renal Harm:
Increased risk
of AKI
?
!
Renal Harm:
Increased risk
of AKI !

37. HF/ASCVD/↑CV risk CKD+HF/ASCVD/↑CV risk CKD
Strong evidence Second line ↓ Albuminuria (?)
Incretin
Mimetics
SGLT2-i
DPP4-i
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Renal Harm:
Increased risk
of AKI
?
!

38. LEADER
(Liraglutide)
SUSTAIN-6
(Semaglutide)
EXSCEL
(Exenatide)
ELIXA
(Lixisenatide)
SCALE
Diabetes
(Liraglutide)
Reduction of
the
composite
renal end
point
New onset
persistent
macroalbuminuria
+
persistent
doubling of SCr,
ESRD or death due
to renal disease
Microalbuminuria
+
doubling of SCr,
creatinine
clearance
>45mL/min/1.73
m2 or the need of
maintenance
dialysis
New-onset
macroalbuminuria
+
decline in eGFR,
need
for renal
replacement
therapy, renal
death
----- -----
Effect on
albuminuria
Reduction of the composite renal end point
was driven by the reduction in new-onset
macroalbuminuria
All the other components did not change significantly
lower increase in
median UACR
although the
median values
at baseline and
follow-up were
clinically similar
showed an 18%
reduction in
albuminuria
compared
N Engl J Med 2016;375:311–322
N Engl J Med 2017; 377: 839–848
NEngl JMed 2016; 375: 1834–1844
NEngl JMed 2015; 373: 2247–2257
Diabetes 2018; 67: 522-P
JAMA 2015; 314: 687–699

39. LEADER
(Liraglutide)
SUSTAIN-6
(Semaglutide)
EXSCEL
(Exenatide)
ELIXA
(Lixisenatide)
SCALE
Diabetes
(Liraglutide)
Reduction of
the
composite
renal end
point
New onset
persistent
macroalbuminuria
+
persistent
doubling of SCr,
ESRD or death due
to renal disease
Microalbuminuria
+
doubling of SCr,
creatinine
clearance
>45mL/min/1.73
m2 or the need of
maintenance
dialysis
New-onset
macroalbuminuria
+
decline in eGFR,
need
for renal
replacement
therapy, renal
death
----- -----
Effect on
albuminuria
Reduction of the composite renal end point
was driven by the reduction in new-onset
macroalbuminuria
All the other components did not change significantly
lower increase in
median UACR
although the
median values
at baseline and
follow-up were
clinically similar
showed an 18%
reduction in
albuminuria
compared
N Engl J Med 2016;375:311–322
N Engl J Med 2017; 377: 839–848
NEngl JMed 2016; 375: 1834–1844
NEngl JMed 2015; 373: 2247–2257
Diabetes 2018; 67: 522-P
JAMA 2015; 314: 687–699
There is aconsiderable evidence demonstrating
that GLP-1 receptor agonists reduces albuminuria
However, evidence of direct benefit on hard renal
outcomes is still lacking

40. SGLT2-i
DPP4-i
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Renal Harm:
Increased risk
of AKI
Incretin
Mimetics
!
HF/ASCVD/↑CV risk CKD+HF/ASCVD/↑CV risk CKD
Strong evidence Second line ↓ Albuminuria (?)

41. SGLT2-i
DPP4-i
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Renal Harm:
Increased risk
of AKI
?
Incretin
Mimetics
!
HF/ASCVD/↑CV risk CKD+HF/ASCVD/↑CV risk CKD
Strong evidence Second line ↓ Albuminuria (?)

42. SGLT2-i
DPP4-i
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Renal Harm:
Increased risk
of AKI
?
CV effect:
vs placebo:
Neutral (except
saxagliptin)
vs non-DPP4-i:
• Lower risk of CVD
• Linagliptin not inferior for glimepride
Renal effect (vs placebo):
● Improve albuminuria ● No effect on CKD progression
Incretin
Mimetics
!
HF/ASCVD/↑CV risk CKD+HF/ASCVD/↑CV risk CKD
Strong evidence Second line ↓ Albuminuria (?)

43. DPP4-IvsPlacebo
N Engl J Med.. 2013 Oct 3;369(14):1317-26 N Engl J Med. 2015 Jul 16;373(3):232-42
Lancet. 2015 May 23;385(9982):2067-76 JAMA. 2019 Jan 1;321(1):69-79
Diabetes Obes Metab. 2010 Jun;12(6):485-94

44. DPP4-IvsPlacebo
Trial SAVOR-TIMI
Trial
EXAMINE
Trial
TECOS CARMELINA Meta-
analysis
DPP4-i Saxagliptin Alogliptin Sitagliptin Linagliptin Vildagliptin
Rate of
hospitalization
for heart
failure
increased by
27%
3.1 vs 2.9%
with placebo,
p=0.657*
did not increase
CV mortality have not demonstrated a reduced or increased risk of
cardiovascular or cerebrovascular mortality
*Post hoc analysis: Lancet. 2015 May 23;385(9982):2067-76

45. DPP4-IvsPlacebo
Trial SAVOR-TIMI
Trial
EXAMINE
Trial
TECOS CARMELINA Meta-
analysis
DPP4-i Saxagliptin Alogliptin Sitagliptin Linagliptin Vildagliptin
Rate of
hospitalization
for heart
failure
increased by
27%
3.1 vs 2.9%
with placebo,
p=0.657*
did not increase
CV mortality have not demonstrated a reduced or increased risk of
cardiovascular or cerebrovascular mortality
*Post hoc analysis: Lancet. 2015 May 23;385(9982):2067-76
4-5-2016

46. DPP4-IvsPlacebo
Trial SAVOR-TIMI
Trial
EXAMINE
Trial
TECOS CARMELINA Meta-
analysis
DPP4-i Saxagliptin Alogliptin Sitagliptin Linagliptin Vildagliptin
Rate of
hospitalization
for heart
failure
increased by
27%
3.1 vs 2.9%
with placebo,
p=0.657*
did not increase
CV mortality have not demonstrated a reduced or increased risk of
cardiovascular or cerebrovascular mortality
*Post hoc analysis: Lancet. 2015 May 23;385(9982):2067-76
4-5-2016
Subgroup analysis of the EXAMINE trial → an increased risk of CV death was observed
in individuals with recent non-fatal CV event (specifically heart failure), compared with
those who did not experience a CV event during the study
Diabetes Care. 2016 Jul;39 (7):1267–1273

47. SGLT2-i
DPP4-i
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death (vs placebo)
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Renal Harm:
Increased risk
of AKI
?
CV effect:
vs placebo:
Neutral (except
saxa/alogliptin)
vs non-DPP4-i:
• Lower risk of CVD
• Linagliptin not inferior for glimepride
Renal effect (vs placebo):
● Improve albuminuria ● No effect on CKD progression
Incretin
Mimetics
!
HF/ASCVD/↑CV risk CKD+HF/ASCVD/↑CV risk CKD
Strong evidence Second line ↓ Albuminuria (?)

48. SGLT2-i
DPP4-i
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death (vs placebo)
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Renal Harm:
Increased risk
of AKI
?
CV effect:
vs placebo:
Neutral (except
saxa/alogliptin)
vs non-DPP4-i:
• Lower risk of CVD
• Linagliptin not inferior for glimepride
Renal effect (vs placebo):
● Improve albuminuria ● No effect on CKD progression
Incretin
Mimetics
!
HF/ASCVD/↑CV risk CKD+HF/ASCVD/↑CV risk CKD
Strong evidence Second line ↓ Albuminuria (?)

49. DPP4-IvsNon-DPP4-i
113 051 patients
2016 Mar 1;15:41
123,050 patients

50. DPP4-IvsNon-DPP4-i
113 051 patients
2016 Mar 1;15:41
123,050 patients
DPP4 inhibitors vs. non-DPP4-I & insulin when added as
second-line therapy to metformin:
DPP4 demonstrated a lower risk for:
• CVD
• Stroke
• MACE
• All-cause mortality

51. DPP4-IvsNon-DPP4-i
Noninferior risk
of a composite
cardiovascular
outcome
2019 Sep 19

52. SGLT2-i
DPP4-i
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death (vs placebo)
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Renal Harm:
Increased risk
of AKI
?
CV effect:
vs placebo:
Neutral (except
saxa/alogliptin)
vs non-DPP4-i:
• Lower risk of CVD
• Linagliptin not inferior to glimepride
Renal effect (vs placebo):
● Improve albuminuria ● No effect on CKD progression
Incretin
Mimetics
!
HF/ASCVD/↑CV risk CKD+HF/ASCVD/↑CV risk CKD
Strong evidence Second line ↓ Albuminuria (?)

53. SGLT2-i
DPP4-i
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death (vs placebo)
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Renal Harm:
Increased risk
of AKI
?
CV effect:
vs placebo:
Neutral (except
saxa/alogliptin)
vs non-DPP4-i:
• Lower risk of CVD
• Linagliptin not inferior to glimepride
Renal effect (vs placebo):
● Improve albuminuria ● No effect on CKD progression
Incretin
Mimetics
!
HF/ASCVD/↑CV risk CKD+HF/ASCVD/↑CV risk CKD
Strong evidence Second line ↓ Albuminuria (?)

54. DPP4-IvsPlacebo
N Engl J Med.. 2013 Oct 3;369(14):1317-26 N Engl J Med. 2015 Jul 16;373(3):232-42
Lancet. 2015 May 23;385(9982):2067-76 JAMA. 2019 Jan 1;321(1):69-79
Diabetes Obes Metab. 2010 Jun;12(6):485-94

55. DPP4-IvsPlacebo
Trial SAVOR-TIMI Trial TECOS CARMELINA
DPP4-i Saxagliptin Sitagliptin Linagliptin
Albuminuria UACR improved * ------ Decreased albuminturia
progression
Renal
outcomes
no difference*
(including doubling
of serum creatinine or the
initiation of hemodialysis)
no
difference**
no difference
(risk of ESRD, death due to kidney
failure, sustained
decrease of ≥40% in eGFR )
*Post hoc analysis: Diabetes Care. 2017 Jan;40(1):69–76
**Post hoc analysis: Diabetes Care. 2016 Dec;39 (12):2304–2310

56. SGLT2-i
DPP4-i
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death (vs placebo)
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Renal Harm:
Increased risk
of AKI
?
CV effect:
vs placebo:
Neutral (except
saxa/alogliptin)
vs non-DPP4-i:
• Lower risk of CVD
• Linagliptin not inferior to glimepride
Renal effect (vs placebo):
● Improve albuminuria ● No effect on CKD progression
Incretin
Mimetics
!
HF/ASCVD/↑CV risk CKD+HF/ASCVD/↑CV risk CKD
Strong evidence Second line ↓ Albuminuria (?)

57. SGLT2-i
Incretin
Mimetics
DPP4-i
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death (vs placebo)
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Renal Harm:
Increased risk
of AKI
CV effect:
vs placebo:
Neutral (except
saxa/alogliptin)
vs non-DPP4-i:
• Lower risk of CVD
• Linagliptin not inferior to glimepride
Renal effect (vs placebo):
● Improve albuminuria ● No effect on CKD progression
!
HF/ASCVD/↑CV risk CKD+HF/ASCVD/↑CV risk CKD
Strong evidence Second line ↓ Albuminuria (?)

58. SGLT2-i
DPP4-i
Incretin
Mimetics
• Evidence of superiority or
inferiority?
• Limitations to use?
• Summary & suggested
approach?
Talk Outline
Renal dose
modification
S.E. &
Precautions

59. SGLT2-i ≥ 60
ml/min
45 - 59
ml/min
30 - 45
ml/min
< 30
ml/min
Cana-
gliflozin
No dose
modific-
ation
100 mg once
daily
- Don’t initiate
- Not
recommended if
eGFR is persistently
< 45 ml/min
Contrain-
dicated
Empa-
gliflozin
No dose
modific-
ation
No dose
modification
- Don’t initiate
- Not
recommended if
eGFR is persistently
< 45 ml/min
Contrain-
dicated
Dapa-
gliflozin
No dose
modific-
ation
- Don’t initiate
- Not
recommended
if eGFR is
persistently <60
ml/min
Contraindicated Contrain-
dicated
DPP4-i
> 50
ml/min
30 - 50
ml/min
< 30 ml/min
(dialyzability)
Sita-
gliptin
100
mg
50
mg
25 mg
(3.5-
13.5%)
Alo-
gliptin
25
mg
12.5
mg
6.25 mg
(3%)
Vilda-
gliptin
100
mg
50
mg
50 mg
(7.2%)
Saxa-
gliptin
5
mg
2.5
mg
2.5 mg
(23%)
Ana-
gliptin
200
mg
200
mg
100 mg
(not
known)
Lina-
gliptin
5
mg
5
mg
5mg
(non
dialyzable)
Teneli-
gliptin
20
mg
20
mg
20mg
(15.6%)

60. 2017 Oct;13(10):605-628

61. SGLT2-i
DPP4-i
Incretin
Mimetics
• Evidence of superiority or
inferiority?
• Limitations to use?
• Summary & suggested
approach?
Talk Outline
Renal dose
modification
S.E. &
Precautions

62. SGLT2-i S.E. and Precautions
 AKI risk increased !
 Genital infections
 Necrotizing fasciitis of the
perineum (rare)
 Euglycemic ketoacidosis
 Amputation?
 Fracture risk?
 Dapagliflozin: Bladder cancer?
DPP4-i
S.E. and Precautions
 Saxagliptin and Alogliptin increase
HF hospitalization
 Pancreatitis
 IBD (specifically ulcerative colitis)
 Joint pain (history of joint pain
should not exclude the use of
DPP4-i)
 Bullous pemphigoid (vildagliptin
and less so linagliptin)
 Fracture risk (lower with alogliptin)

63. SGLT2-i S.E. and Precautions
 AKI risk increased !
 Genital infections
 Necrotizing fasciitis of the
perineum (rare)
 Euglycemic ketoacidosis
 Amputation?
 Fracture risk?
 Dapagliflozin: Bladder cancer?
N Engl J Med. 2015 Nov;373(22):2117–2128
N Engl J Med. 2017 Aug;377(7):644–657
N Engl J Med. 2019 Jan;380(4):347–357
An increased incidence of
UTI was not confirmed in
most trials
N Engl J Med. 2015 Nov;373(22):2117–2128
N Engl J Med. 2017 Aug;377(7):644–657
N Engl J Med. 2019 Jan;380 (4):347–357
DPP4-i
S.E. and Precautions
 Saxagliptin and Alogliptin increase
HF hospitalization
 Pancreatitis
 IBD (specifically ulcerative colitis)
 Joint pain (history of joint pain
should not exclude the use of
DPP4-i)
 Bullous pemphigoid (vildagliptin
and less so linagliptin)
 Fracture risk (lower with alogliptin)

64. SGLT2-i S.E. and Precautions
 AKI risk increased !
 Genital infections
 Necrotizing fasciitis of the
perineum (rare)
 Euglycemic ketoacidosis
 Amputation?
 Fracture risk?
 Dapagliflozin: Bladder cancer?
FDA. 2018 [cited 2019 Feb 8]. Available from:
https://www.fda.gov/Drugs/DrugSafety/ucm
617360.htm
DPP4-i
S.E. and Precautions
 Saxagliptin and Alogliptin increase
HF hospitalization
 Pancreatitis
 IBD (specifically ulcerative colitis)
 Joint pain (history of joint pain
should not exclude the use of
DPP4-i)
 Bullous pemphigoid (vildagliptin
and less so linagliptin)
 Fracture risk (lower with alogliptin)

65. SGLT2-i S.E. and Precautions
 AKI risk increased !
 Genital infections
 Necrotizing fasciitis of the
perineum (rare)
 Euglycemic ketoacidosis
 Amputation?
 Fracture risk?
 Dapagliflozin: Bladder cancer?
N Engl J Med. 2019 Jan;380
FDA. 2015 [cited 2019 Feb 8]. Available from:
https://www.fda.gov/downloads/Drugs/DrugSafety/UCM446954.pdf
Cardiovasc Diabetol. 2014;13:65.
J Clin Endocrinol Metab. 2015 Aug;100(8):2849–2852.
DPP4-i
S.E. and Precautions
 Saxagliptin and Alogliptin increase
HF hospitalization
 Pancreatitis
 IBD (specifically ulcerative colitis)
 Joint pain (history of joint pain
should not exclude the use of
DPP4-i)
 Bullous pemphigoid (vildagliptin
and less so linagliptin)
 Fracture risk (lower with alogliptin)

66. SGLT2-i S.E. and Precautions
 AKI risk increased !
 Genital infections
 Necrotizing fasciitis of the
perineum (rare)
 Euglycemic ketoacidosis
 Amputation (Canagliflozin)
 Fracture risk?
 Dapagliflozin: Bladder cancer?
N Engl J Med. 2017 Aug;377(7):644–657
N Engl J Med. 2015 Nov;373(22):2117–2128
N Engl J Med. 2019 Jan;380(4):347–357
FDA. 2017 [cited 2019 Feb 8]. Available from:
https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm
Diabetes Obes Metab. 2018 Jun;20(6):1531–1534.
Diabetes Obes Metab. 2018 Nov;20(11):2585–2597.
DPP4-i
S.E. and Precautions
 Saxagliptin and Alogliptin increase
HF hospitalization
 Pancreatitis
 IBD (specifically ulcerative colitis)
 Joint pain (history of joint pain
should not exclude the use of
DPP4-i)
 Bullous pemphigoid (vildagliptin
and less so linagliptin)
 Fracture risk (lower with alogliptin)
Risk factors: prior amputation, peripheral
neuropathy, peripheral vascular disease or
smoking
5-16-2017

67. SGLT2-i S.E. and Precautions
 AKI risk increased !
 Genital infections
 Necrotizing fasciitis of the
perineum (rare)
 Euglycemic ketoacidosis
 Amputation (Canagliflozin)
 Fracture risk
 Dapagliflozin: Bladder cancer?Lancet Diabetes Endocrinol. 2015 Jan;3(1):8–10
Kidney Int. 2014 Apr;85(4):962–971
J Clin Endocrinol Metab. 2016 Jan;101(1):157–166.
Ann Intern Med. 2019;170:155
N Engl J Med. 2017 Aug;377(7):644–657
DPP4-i
S.E. and Precautions
 Saxagliptin and Alogliptin increase
HF hospitalization
 Pancreatitis
 IBD (specifically ulcerative colitis)
 Joint pain (history of joint pain
should not exclude the use of
DPP4-i)
 Bullous pemphigoid (vildagliptin
and less so linagliptin)
 Fracture risk (lower with alogliptin)

68. SGLT2-i S.E. and Precautions
 AKI risk increased !
 Genital infections
 Necrotizing fasciitis of the
perineum (rare)
 Euglycemic ketoacidosis
 Amputation (Canagliflozin)
 Fracture risk
DPP4-i
S.E. and Precautions
 Saxagliptin and Alogliptin increase
HF hospitalization
 Pancreatitis
 IBD (specifically ulcerative colitis)
 Joint pain (history of joint pain
should not exclude the use of
DPP4-i)
 Bullous pemphigoid (vildagliptin
and less so linagliptin)
 Fracture risk (lower with alogliptin)
Diabetes Care. 2017 Feb;40(2):164–170
Diabetes Care. 2017 Feb;40(2):284–286
Diabetes Obes Metab. 2016 Mar;18(3):295–299
JAMA. 2019 Jan 1;321(1):69–79

69. SGLT2-i S.E. and Precautions
 AKI risk increased !
 Genital infections
 Necrotizing fasciitis of the
perineum (rare)
 Euglycemic ketoacidosis
 Amputation (Canagliflozin)
 Fracture risk
DPP4-i
S.E. and Precautions
 Saxagliptin and Alogliptin increase
HF hospitalization
 Pancreatitis
 IBD (specifically ulcerative colitis)
 Joint pain (history of joint pain
should not exclude the use of
DPP4-i)
 Bullous pemphigoid (vildagliptin
and less so linagliptin)
 Fracture risk (lower with alogliptin)
N Engl J Med. 2014 Feb;370(9):794–797
Sci Rep. 2018 Jan;8(1):782
Cardiovasc Diabetol. 2017 Mar;16(1):31

70. SGLT2-i S.E. and Precautions
 AKI risk increased !
 Genital infections
 Necrotizing fasciitis of the
perineum (rare)
 Euglycemic ketoacidosis
 Amputation (Canagliflozin)
 Fracture risk
DPP4-i
S.E. and Precautions
 Saxagliptin and Alogliptin increase
HF hospitalization
 Pancreatitis
 IBD (specifically ulcerative colitis)
 Joint pain (history of joint pain
should not exclude the use of
DPP4-i)
 Bullous pemphigoid (vildagliptin
and less so linagliptin)
 Fracture risk (lower with alogliptin)
FDA. 2015 [cited 2019 Feb 8]. Available from:
https://www.fda.gov/Drugs/DrugSafety/ucm459579.htm
Diabetes Metab. 2017 Dec;43(6):493–500
Drug Saf. 2016 May;39(5):401–407

71. SGLT2-i S.E. and Precautions
 AKI risk increased !
 Genital infections
 Necrotizing fasciitis of the
perineum (rare)
 Euglycemic ketoacidosis
 Amputation (Canagliflozin)
 Fracture risk
DPP4-i
S.E. and Precautions
 Saxagliptin and Alogliptin increase
HF hospitalization
 Pancreatitis
 IBD (specifically ulcerative colitis)
 Joint pain (history of joint pain
should not exclude the use of
DPP4-i)
 Bullous pemphigoid (vildagliptin
and less so linagliptin)
 Fracture risk (lower with alogliptin)JAMA Dermatol. 2018 Oct;154(10):1152–1158
JAMA Dermatol. 2019 Feb;155(2):172–177

72. SGLT2-i S.E. and Precautions
 AKI risk increased !
 Genital infections
 Necrotizing fasciitis of the
perineum (rare)
 Euglycemic ketoacidosis
 Amputation (Canagliflozin)
 Fracture risk
DPP4-i
S.E. and Precautions
 Saxagliptin and Alogliptin increase
HF hospitalization
 Pancreatitis
 IBD (specifically ulcerative colitis)
 Joint pain (history of joint pain
should not exclude the use of
DPP4-i)
 Bullous pemphigoid (vildagliptin
and less so linagliptin)
 Fracture risk (lower with alogliptin)
PLoS One. 2017;12(12):e0187537

73. 2014 Fall-Winter; 11(3): 202–230
Incretin
Mimetics

74. 2014 Fall-Winter; 11(3): 202–230
Incretin
Mimetics
The most common adverse effect of GLP-1R agonists is
nausea, with incidence rates varying from 25–60%, and
vomiting in 5–15%
2017 Oct;13(10):605-628

75. SGLT2-i
DPP4-i
Incretin
Mimetics
• Evidence of superiority or
inferiority?
• Limitations to use?
• Summary & suggested
approach?
Talk Outline
Renal dose
modification
S.E. &
Precautions

76. SGLT2-i
Incretin
Mimetics
DPP4-i
CV Benefit:
vs placebo:
 ↓ risk of composite CV events
 ↓ risk of CV death (vs placebo)
vs DPP4-i:
↓ hospitalization for
HF
Renal Benefit (vs placebo):
• Reno-protective effect
• Delay CKD progression
Renal Harm:
Increased risk
of AKI
CV effect:
vs placebo:
Neutral (except
saxa/alogliptin)
vs non-DPP4-i:
• Lower risk of CVD
• Linagliptin not inferior to glimepride
Renal effect (vs placebo):
● Improve albuminuria ● No effect on CKD progression
!
HF/ASCVD/↑CV risk CKD+HF/ASCVD/↑CV risk CKD
Strong evidence Second line ↓ Albuminuria (?)

77. SGLT2-i ≥ 60
ml/min
45 - 59
ml/min
30 - 45
ml/min
< 30
ml/min
Cana-
gliflozin
No dose
modific-
ation
100 mg once
daily
- Don’t initiate
- Not
recommended if
eGFR is persistently
< 45 ml/min
Contrain-
dicated
Empa-
gliflozin
No dose
modific-
ation
No dose
modification
- Don’t initiate
- Not
recommended if
eGFR is persistently
< 45 ml/min
Contrain-
dicated
Dapa-
gliflozin
No dose
modific-
ation
- Don’t initiate
- Not
recommended
if eGFR is
persistently <60
ml/min
Contraindicated Contrain-
dicated
DPP4-i
> 50
ml/min
30 - 50
ml/min
< 30 ml/min
(dialyzability)
Sita-
gliptin
100
mg
50
mg
25 mg
(3.5-
13.5%)
Alo-
gliptin
25
mg
12.5
mg
6.25 mg
(3%)
Vilda-
gliptin
100
mg
50
mg
50 mg
(7.2%)
Saxa-
gliptin
5
mg
2.5
mg
2.5 mg
(23%)
Ana-
gliptin
200
mg
200
mg
100 mg
(not
known)
Lina-
gliptin
5
mg
5
mg
5mg
(non
dialyzable)
Teneli-
gliptin
20
mg
20
mg
20mg
(15.6%)

78. 2017 Oct;13(10):605-628

79. SGLT2-i
S.E. and Precautions
 AKI risk increased !
 Genital infections
 Necrotizing fasciitis of the
perineum (rare)
 Euglycemic ketoacidosis
 Amputation (Canagliflozin)
 Fracture risk
DPP4-i
S.E. and Precautions
 Alogliptin and Saxagliptin increases
HF hospitalization
 Pancreatitis
 Pancreatic cancer??
 IBD (specifically ulcerative colitis)
 Joint pain (history of joint pain
should not exclude the use of
DPP4-i)
 Bullous pemphigoid (vildagliptin
and less so linagliptin)
 Fracture risk (lower with alogliptin)

80. 2014 Fall-Winter; 11(3): 202–230
Incretin
Mimetics
The most common adverse effect of GLP-1R agonists is nausea, with
incidence rates varying from 25–60%, and vomiting in 5–15%
2017 Oct;13(10):605-628

81. If in need to add on a drug to metformin or if metformin is
contraindicated
Use SGLT2-i if there is no
eGFR limitations and/ or
contraindications
(osteoporosis, history of
ketosis or mycotic
infections)
If C.I. or eGFR limitation to
SGLT2-i
HF/ASCVD or high
CV risk
Yes
Use incretins if no C.I. or eGFR
limitations (liraglutide >
semaglutide > exenatide
extended release)
If C.I. or eGFR
limitations to
incretins
No
Is there any
contraindications to
DPP4- use (Pancreatitis,
Inflammatory bowel
disease, fracture risk)?
Yes:
Use other hypoglycemic
medications
No:
Use DPP4-I (↓ albuminuria)
vs other oral hypoglycemic
Hypoglycemic medications use in CKD
if no C.I. to
incretin
mimetics?
(↓ Albuminuria)

82. If in need to add on a drug to metformin or if metformin is
contraindicated
Use SGLT2-i if there is no
eGFR limitations and/ or
contraindications
(osteoporosis, history of
ketosis or mycotic
infections)
If C.I. or eGFR limitation to
SGLT2-i
HF/ASCVD or high
CV risk
Yes
Use incretins if no C.I. or eGFR
limitations (liraglutide >
semaglutide > exenatide
extended release)
If C.I. or eGFR
limitations to
incretins
No
Is there any
contraindications to
DPP4- use (Pancreatitis,
Inflammatory bowel
disease, fracture risk)?
Yes:
Use other hypoglycemic
medications
No:
Use DPP4-I (↓ albuminuria)
vs other oral hypoglycemic
Hypoglycemic medications use in CKD
if no C.I. to
incretin
mimetics?
(↓ Albuminuria)DPP-4 inhibitors and SGLT-2 inhibitors are at least 4–5
times the cost of metformin or SU therapy
ADA. Diabetes Care. 2018 Jan;41(Suppl 1):S73–85.

83. The treatment algorithm is an individualized
program by which patient factors that include:
tolerance, cost, availability, and preference are
taken into consideration

84. Thank You