The CREDENCE trial evaluated the effect of canagliflozin vs placebo on renal outcomes in patients with type 2 diabetes and chronic kidney disease. Over 2.6 years of follow up: 1) Canagliflozin reduced the composite outcome of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death by 30% compared to placebo. 2) Canagliflozin also reduced cardiovascular death, myocardial infarction, stroke or hospitalization for heart failure by 30% compared to placebo. 3) The trial demonstrated that canagliflozin provided renoprotective and cardiovascular benefits in patients with type 2 diabetes and chronic kidney disease.

1. Cardiovascular Outcome Trails in SGLT2
Inhibitors
Dr. Rohan Sonawane
MBBS, MD, DNB (Interventional Cardiology reg)

2. Urinary glucose excretion via SGLT2 inhibition
SGLT2
SGLT2
inhibitor
SGLT1
SGLT2 inhibitors
reduce glucose
reabsorption
in the proximal
tubule, leading to
urinary glucose
excretion* and
osmotic diuresis
Filtered glucose load >
180 g/day

3. 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
Pharmacological properties of available SGLT2 inhibitors

4.  Weight
 Visceral
adiposity
 Blood pressure
 Arterial
stiffness
 Glucose
 Insulin
 Albuminuria
 Uric Acid
 LDL-C
 HDL-C
 Triglycerides
 Oxidative
stress
 SNS
activity (?)
Effects of SGLT2 inhibitors on CV risk

5. CV safety trials
CANVAS-R8
(n= 5700)
Albuminuria
2013 2014 2015 2016 2017 2018 2019
SAVOR-TIMI531
(n= 16,492)
1,222 3P-MACE
EXAMINE2
(n= 5380)
621 3P-MACE
TECOS4
(n= 14,724)
≥ 1300 4P-MACE
LEADER6
(n= 9340)
≥ 611 3P-MACE
SUSTAIN-67
(n= 3297)
3P-MACE
DECLARE-TIMI5815
(n= 17,150)
≥ 1390 3P-MACE
EMPA-REG OUTCOME®5
(n= 7034)
≥ 691 3P-MACE
CANVAS10
(n= 4365)
≥ 420 3P-MACE
CREDENCE17
(n= 3700)
Renal+ 5P-MACE
CAROLINA®11
(n= 6000)
≥ 631 4P-MACE
ITCA CVOT9
(n= 4000)
4P-MACE
EXSCEL14
(n= 14,000)
≥ 1591 3P-MACE
DPP4inhibitorCVOTs
SGLT2 inhibitorCVOTs
GLP1 CVOTs
ErtugliflozinCVOT18
(n= 3900)
3P-MACE
OMNEON13
(n= 4000)
4P-MACE
CARMELINA12
(n= 8300)
4P-MACE + renal
REWIND16
(n= 9622)
≥ 1067 3P-MACE
2021
ELIXA3
(n= 6068)
≥ 844 4P-MACE

6. Empagliflozin Cardiovascular Outcome Event Trial in Type 2
Diabetes Mellitus Patients - EMPA-REG OUTCOME 2015
Goal :
To assess the cardiovascular safety of empagliflozin, a
sodium–glucose cotransporter 2 inhibitor, in patients with type 2
diabetes mellitus (DM2) at high risk for CV events.

7. • Randomized in a 1:1:1 fashion
1. Empagliflozin 10 mg (n = 2,345),
2. Empagliflozin 25 mg (n = 2,342),
3. Matching placebo (n = 2,333).
• Total number of enrolees: 7,028
• Duration of follow-up: 3.1 years
• Mean patient age: 63.1 years
• Percentage female: 28%

8. Inclusion criteria:
Age ≥18 years
DM2
Glycosylated hemoglobin (HbA1c)
- ≥7.0% and ≤10% for patients on background therapy
- HbA1c ≥7.0% & ≤9.0% for drug-naive patients
- Background glucose-lowering therapy unchanged for
≥12 weeks prior to randomization
-In the case of insulin, unchanged by >10% from the
dose at randomization in previous 12 weeks
BMI ≤ 45 kg/m2
GFR >30
Established cardiovascular disease

9. Exclusion criteria:
• Uncontrolled hyperglycemia (glucose level >240 mg/dl after an overnight fast)
• Liver disease
• Planned cardiac surgery or angioplasty within 3 months
• Bariatric / GI surgery within the past 2 years
• Blood disorders causing hemolysis e.g., malaria, hemolytic anemia
• History of cancer and/or treatment for cancer within the last 5 years
• Treatment with anti-obesity drugs (e.g., sibutramine, orlistat) 3 months
• Current treatment with systemic steroids or any other uncontrolled endocrine
disorder except DM2
• Alcohol or drug abuse within 3 months
• Acute coronary syndrome, stroke, or transient ischemic attack within 2 months
prior to informed consent

10. Primary outcome :
CV death, nonfatal MI, or stroke for empagliflozin vs. placebo: 10.5% vs. 12.1%
hazard ratio (HR) 0.86, 95% confidence interval 0.74-0.99
p < 0.001 for noninferiority;
p = 0.04 for superiority.
For CV death: 3.7% vs. 5.9%, p < 0.001
all MI: 4.8% vs. 5.4%, p = 0.23
all stroke: 3.5% vs. 3.0%, p = 0.26
For primary endpoint, results were similar for two doses of empagliflozin vs. placebo

11. Secondary outcomes:
• All-cause mortality: 3.8% vs. 5.1%, p < 0.01
• CHF hospitalization: 2.7% vs. 4.1%, p = 0.002
• CHF hospitalization or CV death: 5.7% vs. 8.5%, p < 0.001
• Coronary revascularization: 7% vs. 8%, p = 0.11
• HbA1c at 12 weeks for 10 mg empagliflozin vs. placebo: -0.54%; at 206
weeks: -0.24%
• HbA1c at 12 weeks for 25 mg empagliflozin vs. placebo: -0.6%; at 206 weeks:
-0.36%
• Confirmed hypoglycemic event: 27.8% vs. 27.9%
• UTI: 18% vs. 18.1%, p > 0.05
• genital infection: 6.4% vs. 1.8%, p < 0.001

12. Interpretation:
• Empagliflozin superior to placebo in improving glycemic control and
reducing CV events in patients with DM2 and established CVD
• Significant mortality benefit with empagliflozin
• One of the first large-scale DM2 trials to show an improvement in
hard CV outcomes with simultaneous improvements in glycemic
control in a high-risk population.

13. Canagliflozin Cardiovascular Assessment Study – CANVAS
2017
Goal:
To compare effects of Canagliflozin vs placebo on CV,
renal and safety outcomes among secondary and primary
prevention participants in Type 2 DM
Patients with type 2 diabetes were randomized
Canagliflozin (n = 5,795) versus placebo (n = 4,347)
Patients in canagliflozin arm received 300 mg daily or 100 mg
daily.

14. Inclusion criteria:
• Patients with type 2 DM with high CV risk
• ≥ 30 years of age
• History of symptomatic atherosclerotic cardiovascular disease
• ≥50 years of age and 2+ of the following:
1. Diabetes duration >10 years
2. SBP >140 mm Hg on antihypertensive therapy
3. Current smoking
4. Albuminuria
5. HDL cholesterol <38.7 mg/dl

15. Primary Outcome…
• Incidence of CV death, MI, or stroke (26.9 versus 31.5 participants per
1,000 patient-years of the placebo group)
p = 0.02 for superiority,
p < 0.001 for noninferiority.
• The benefit for canagliflozin appeared to be similar for patients with HFrEF
and those with HFpEF.

16. Secondary outcomes:
- Reduction in cardiovascular death or hospitalization for heart failure
appeared to be greater among those with a history of heart failure (hazard ratio
[HR] 0.61, 95% confidence interval [CI] 0.46- 0.80), compared to those with no
history of heart failure (HR 0.87, 95% CI 0.72- 1.06; p for interaction 0.021).
- Amputation: 6.3 vs 3.4 per 1,000 patient-years (p < 0.05)
- Progression of albuminuria: 89.4 vs 128.7 participants per 1,000 patient-
years (p < 0.05)

17. Hazard ratio (95% CI) P value
Primary composite endpoint* 0.86 (0.75-0.97) 0.02†
CV death 0.87 (0.72-1.06)
Nonfatal MI 0.85 (0.69-1.05)
Nonfatal stroke 0.90 (0.71-1.15)
Fatal or nonfatal MI 0.89 (0.73-1.09)
Fatal or nonfatal stroke 0.87 (0.69-1.09)
HF hospitalization 0.67 (0.52-0.87)
CV death or HF hospitalization 0.78 (0.67-0.91)
All-cause death 0.87 (0.74-1.01)
Progression of albuminuria 0.73 (0.67-0.79)
40% reduction in eGFR, renal replacement
therapy, or renal death
0.60 (0.47-0.77)
17
Outcomes of CANVAS
(N=10,142)
0.00 0.50 1.00 1.50
Favors canagliflozin
Median follow-up: 2.4 years

18. CANVAS trial showed that….
• Canagliflozin was efficacious for the prevention of CV events
• So its primary objective of demonstrating cardiovascular safety was met
• Canagliflozin use was associated with increased risk of amputation which should
be taken into consideration when prescribing this agent

19. Canagliflozin and Renal Events in Diabetes With Established
Nephropathy Clinical Evaluation – CREDENCE- 2019
Goal :
To assess the effect of canagliflozin on renal outcomes among
patients with type 2 diabetes mellitus (DM2) and chronic kidney
disease (CKD).

20. • Patients were randomized in a 1:1 fashion
Canagliflozin 100 mg daily (n = 2,202)
Matching placebo (n = 2,199).
• Total number of enrollees: 4,401
• Duration of follow-up: 2.62 years
• Mean patient age: 63.0 years
• Percentage female: 33.9%

21.  Inclusion criteria:
• Age ≥30 years
• DM2 Glycosylated hemoglobin (HbA1c) of ≥6.5% and ≤12%
• CKD with estimated glomerular filtration rate (eGFR) 30 to <90
• Albuminuria (urinary albumin-to-creatinine ratio >300 to 5000 mg/g)
• Stable dose of an angiotensin-converting enzyme inhibitor (ACEi) or
angiotensin-receptor blocker (ARB) for ≥4 weeks before randomization

22.  Exclusion criteria:
• Nondiabetic kidney disease or type 1 diabetes
• Treated with immunosuppression for kidney disease
• History of dialysis or kidney transplantation
• Dual-agent treatment with an ACEi and an ARB, a direct renin
inhibitor, or a mineralocorticoid-receptor antagonist

23.  Primary Outcome….
For canagliflozin vs. placebo -
- Endstage renal disease
- doubling of serum creatinine
- renal or cardiovascular death
[ 43.2 vs. 61.2 per 1,000 patient-years ] (p = 0.00001)

24.  Secondary Outcome ….
For canagliflozin vs. placebo:
- All-cause mortality [29.0 vs. 35.0/1,000 P-Y (p > 0.05]
- CV death, M.I., stroke, hospitalization for heart failure/unstable angina [27.0
vs. 40.4/1,000 P-Y (p < 0.001)
- Amputation [12.3 vs. 11.2/1,000 P-Y (p > 0.05)
- Reduction in HbA1c at 13 weeks [ 0.31%]

25. Baseline Demographics
Canagliflozin
(n = 2202)
Placebo
(n = 2199)
Hypertension, % 97 97
Heart failure (NYHA I-III), % 15 15
CV disease, % 51 50
Renal and CV protective agents, %
RAAS inhibitor >99.9 99.8
Statin 70 68
Antithrombotic 61 58
Beta blocker 40 40
Diuretic 47 47

26. CV Death or Hospitalization for Heart Failure
0
5
10
15
20
25
0 26 52 78 104 130 156 182
Months since randomization
253 participants
179 participants
Hazard ratio, 0.69 (95% CI, 0.57–0.83)
P <0.001
No. at risk
Placebo 2199 2165 2123 2044 1736 1147 638 170
Canagliflozin 2202 2171 2132 2077 1789 1226 668 199
6 12 18 24 30 36 42
Participants
with
an
event
(%)
Placebo
Canagliflozin

27. Major Cardiovascular Events: CV Death, MI, or Stroke
No. at risk
Placebo 2199 2152 2100 2022 1717 1143 635 168
Canagliflozin 2202 2163 2106 2047 1756 1196 642 198
0
5
10
15
20
25
0 26 52 78 104 130 156 182
Months since randomization
Hazard ratio, 0.80 (95% CI, 0.67–0.95)
P = 0.01
269 participants
217 participants
6 12 18 24 30 36 42
Participants
with
an
event
(%)
Placebo
Canagliflozin

28. Hospitalization for Heart Failure
0
5
10
15
20
25
0 26 52 78 104 130 156 182
Months since randomization
No. at risk
Placebo 2199 2165 2122 2043 1735 1147 638 170
Canagliflozin 2202 2171 2131 2076 1789 1226 668 199
Hazard ratio, 0.61 (95% CI, 0.47–0.80)
P <0.001
141 participants
89 participants
6 12 18 24 30 36 42
Participants
with
an
event
(%)
Placebo
Canagliflozin

29. CV Death
No. at risk
Placebo 2199 2185 2160 2106 1818 1220 688 189
Canagliflozin 2202 2187 2155 2120 1835 1263 687 212
0
5
10
15
20
25
0 26 52 78 104 130 156 182
Months since randomization
140 participants
110 participants
Hazard ratio, 0.78 (95% CI, 0.61–1.00)
P = 0.0502
6 12 18 24 30 36 42
Participants
with
an
event
(%)
Placebo
Canagliflozin

30. Summary
Primary Hazard ratio (95% CI) P value
1. ESKD, doubling of serum creatinine, or renal or CV death 0.70 (0.59–0.82) 0.00001
Secondary
2. CV death or hospitalization for heart failure 0.69 (0.57–0.83) <0.001
3. CV death, MI, or stroke 0.80 (0.67–0.95) 0.01
4. Hospitalization for heart failure 0.61 (0.47–0.80) <0.001
5. ESKD, doubling of serum creatinine, or renal death 0.66 (0.53–0.81) <0.001
6. CV death 0.78 (0.61–1.00) 0.0502
7. All-cause mortality 0.83 (0.68–1.02) –
8. CV death, MI, stroke, hospitalization for heart failure, or hospitalization for
unstable angina
0.74 (0.63–0.86) –

31.  Interpretation:
• Canagliflozin : superior to placebo in improving glycemic control and
reducing adverse renal events in DM2 and established CKD.
• Canagliflozin also reduced CV events.
• No difference in risk was observed with canagliflozin compared with
placebo for:
• Fracture
• Amputation
• All patients were on baseline ACEi/ARB. A similar protective effect on renal
outcomes was noted with empagliflozin in the EMPAREG OUTCOME trial

32. But….
CREDENCE was specifically designed to enroll CKD patients, not
high CV risk patients (as in EMPA-REG OUTCOME).

33. These findings suggest that ….
• Canagliflozin (and SGLT2 agents) may need to be considered routinely
among patients with DM2 and CKD who are already on a renin-
angiotensin system inhibitor.

34. Dapagliflozin Effect on Cardiovascular Events– Thrombolysis in
Myocardial Infarction 58- DECLARE–TIMI 58 - 2019

35. • Goal:
To assess the cardiovascular (CV) safety of dapagliflozin in
patients with type 2 diabetes mellitus (DM2) and either established
CV disease (CVD) or multiple risk factors.

36. • Patients were randomized in a 1:1 fashion
Dapagliflozin 10 mg (n = 8,582)
Matching placebo (n = 8,578).
• Total number of enrollees: 17,160
• Duration of follow-up: 4.2 years
• Mean patient age: 64.0 years
• Percentage female: 37%

37.  Inclusion criteria:
• Age ≥40 years
• DM2 Glycosylated hemoglobin (HbA1c) of ≥6.5% and ≤12%
• Glomerular filtration rate (GFR) of >60
• Established CVD or multiple risk factors including men ≥55 years or
women ≥60 years with hypertension, dyslipidemia, or tobacco use

38.  Exclusion criteria:
• Diagnosis of type 1 DM
• History of bladder cancer
• History of radiation therapy to the lower abdomen or pelvis at any
time
• Chronic cystitis and/or recurrent urinary tract infections
• Pregnant or breast-feeding patients

39. • Primary outcome:
Major adverse cardiac events (MACE) for dapagliflozin vs.
placebo: 8.8% vs. 9.4%,
Hazard ratio (HR) 0.93,
95% confidence interval (CI) 0.841.03,
p < 0.001 for noninferiority;
p = 0.17 for superiority

40.  Secondary outcomes for dapagliflozin vs. placebo:
• Reduction in HbA1c with dapagliflozin: 0.42%
• CV death or heart failure (HF) hospitalization: 4.9% vs. 5.8%, p = 0.005
• HF hospitalization: 2.5% vs. 3.3%, p < 0.005
• All-cause mortality: 6.2% vs. 6.6%, p > 0.05 >40% decrease in GFR,
end-stage renal disease, or death due to renal or CV causes: 4.3% vs.
5.6%, p < 0.05
• Diabetic ketoacidosis: 0.3% vs. 0.1%, p = 0.02
• Genital infections: 0.9% vs. 0.1%, p < 0.001
• Amputation: 1.4% vs. 1.3%, p = 0.53

41. Baseline Characteristics
Full Trial Cohort
N = 17160
Age , Mean (SD) 64 (7)
Female Sex (%) 37
BMI, Mean (SD) 32 (6)
Duration of T2DM, Median (IQR) 11 (6, 16)
HbA1c, Mean (SD) 8.3 (1.2)
eGFR (CKD-EPI), Mean (SD) 85 (16)
Region (%): North America 32
Europe 44
Latin America 11
Asia Pacific 13
Established CV Disease (%) 41
History of Heart Failure (%) 10

42. Baseline Characteristics:
Medication Use
Full Trial Cohort
N = 17160
Glucose lowering therapies (%)
Metformin 82
Insulin 41
Sulfonylurea 43
DPP4 17
GLP-1 RA 4
Cardiovascular Therapies (%)
Antiplatelet 61
ACEI/ARB 81
Beta-blocker 53
Statin or Ezetimibe 75
P=NS for all between treatment arm comparisons

43. Cardiovascular Risk Factors
LSM Difference 1.8 kg (95% CI 1.7-2.0)
All P-values (except BL) <0.001
LSM Difference 0.42% (95% CI 0.40-0.45)
All P-values (except BL) <0.001
HbA1c Weight

44. Cardiovascular Risk Factors
LSM Difference 0.7mmHg (95% CI 0.6-0.9)
LSM Difference 2.7 mmHg (95% CI 2.4-3.0)
All P-values (except BL) <0.001
SBP DBP
All P-values (except BL) <0.001

45. Primary Endpoints
MACE
8.8% vs 9.4%
HR 0.93 (0.84-1.03)
P(Noninferiority) <0.001
P(Superiority) 0.17
CVD/HHF
4.9% vs 5.8%
HR 0.83 (0.73-0.95)
P(Superiority) 0.005

46. Secondary Endpoints
1st Renal Composite EP
40%↓ eGFR, ESRD, Renal or CV death
All-Cause Mortality
4.3% vs. 5.6%
HR 0.76 (0.67-0.87)
P<0.001
6.2% vs 6.6%
HR 0.93 (0.82-1.04)
P=0.20

47. • Patients with prior myocardial infarction (MI): (n = 3,584).
Dapagliflozin reduced the relative risk of MACE by 16% and
absolute risk by 2.6% among patients with prior MI (15.2% vs. 17.8%;
HR 0.84, 95% CI 0.72-0.99, p = 0.039)
No effect in patients without prior MI (7.1% vs. 7.1%; HR 1.00,
95% CI 0.88-1.13, p = 0.97; p-interaction for relative difference 0.11).

48. • Effect of ejection fraction (EF):
3.9% had HF with reduced EF (HFrEF). Dapagliflozin reduced CV
death/hospitalization for HF more in patients with HFrEF (HR 0.62, 95%
CI 0.45-0.86) than in those without HFrEF (HR 0.88, 95% CI 0.76-1.02;
pinteraction 0.046).
It reduced CV death only in patients with HFrEF (HR 0.55, 95% CI
0.34-0.90) but not in those without HFrEF (HR 1.08, 95% CI 0.89-1.31;
p-interaction 0.012).
Similar results were noted for all-cause mortality.

49. • The results of this trial indicate that dapagliflozin is superior to
placebo in improving glycemic control and noninferior but not
superior for reducing MACE in patients with DM2 and high CV risk.
• There was a reduction in HF hospitalizations, Among patients with
HFrEF, dapagliflozin reduced HF hospitalizations, and CV and all-cause
mortality;

50. Summary of CV outcome trials with SGLT2 inhibitors
EMPA-REG OUTCOME®1 CANVAS2
CANVAS-R3 CREDENCE4 DECLARE-
TIMI 585
Interventions Empagliflozin/ placebo Canagliflozin/
placebo
Canagliflozin/
placebo
Canagliflozin/
placebo
Dapagliflozin/ 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 +
macroalbuminuria
High risk for CV events
No. of patients 7034 4339 5700 3627 17,150
Primary outcome 3P-MACE 3P-MACE Progression of
albuminuria
ESKD,
S-creatinine doubling,
renal/CV death
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 +
revascularisation
Target no.
of events
691 ≥ 420 TBD TBD 1390
Estimated median FU ~3 years 6–7 years 3 years ~4 years 4–5 years
Estimated completion 2015 Apr 2017 2017 2019 2019
3P-MACE- 3-point major adverse CV events (CV death, non-fatal myocardial infarction or non-fatal stroke);
4P-MACE- 4-point major adverse CV events (CV death, non-fatal myocardial infarction, non-fatal stroke or unstable
angina requiring hospitalisation);

51. • Patients with type 2 DM are at high risk for development of
complications from atherosclerotic CV events and heart failure.
• CV outcomes trials with SGLT-2i have shown reductions in CV and
renal events predominantly in secondary prevention patients
• safety questions with SGLT2i in other trials have been raised related
to amputation, stroke and DKA.