Kirkwood F. Adams, Jr. MD
Associate Professor of Medicine and Radiology
HF Management 2019
Amelia Island Meeting
Cardiovascular Protection by
SGLT2 Inhibitors – Possible
Mechanisms Circa 2019
Dramatic Benefits of SGLT2 Inibitors CV On
CV Death and CHF Hospitalization
Verma and McMurray (2018) Diabetologia DOI 10.1007/s00125-018-4670-7 © Springer-Verlag GmbH Germany, part of Springer Nature 2018
The cardiovascular benefits with empagliflozin (EMPA-REG OUTCOME trial) and canagliflozin (CANVAS) in participants with and without a history of heart failure
SGLT2 Inhibitors – Mechanisms CV Protection
SNS
activity (?)
SGLT2 inhibitors modulate a range of factors
related to CV riskBased on clinical and mechanistic studies
Inzucchi et al. Diab Vasc Dis Res 2015;12:90‒100.
Weight
Visceral
adiposity
Blood pressure
Arterial
stiffness
Glucose
Insulin
Albuminuria
Uric Acid
Novel
Pathways (?)
LDL-C
HDL-C
Triglycerides
Oxidative
stress
SNS
activity (?)
SGLT2
Inhibitors –
Potential
Role
Blocking the
Sodium-
Hydrogen
Exchanger
SGLT2 Inhibitors – Potential Role of
Sodium-Hydrogen Exchanger
Verma and McMurray (2018) Diabetologia DOI 10.1007/s00125-018-4670-7 © G. Oomen 2018
SGLT2 inhibition and direct effects on Na+/H+ exchange in the myocardium
Benefits
on Renal
Outcomes
with
SGLT2
Inhibitors
Emap and
Cana
SGLT2 Inhibitors – Renal Protection –
Reduce Decline in eGFR
Urinary glucose excretion via SGLT2
inhibition
Bakris et al. Kidney Int 2009;75:1272–7.
SGLT2SGLT2
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
Verma and McMurray (2018) Diabetologia DOI 10.1007/s00125-018-4670-7 © G. Oomen 2018
SGLT2 inhibitors improve ventricular loading conditions
SGLT2 and Tubular Glomerular Feedback
SGLT2 and Tubular Glomerular Feedback
Potential Renal Benefits SGLT2 Inibitors
Verma and McMurray (2018) Diabetologia DOI 10.1007/s00125-018-4670-7 © G. Oomen 2018
SGLT2 inhibitors may differentially regulate the interstitial vs intravascular compartment when compared with loop diuretics
Loop diureticsSGLT2 inhibitors
Favorable Out Weighs Unfavorable Effects
of SGLT2 Inhibition
Broader Potential for SGLT2 Inibition – At
Risk of CVD
SGLT2 Inhibitors – Mechanisms Renal Protection
SNS
activity (?)
SGLT2 inhibitors modulate a range of factors
related to CV riskBased on clinical and mechanistic studies
24
Inzucchi et al. Diab Vasc Dis Res 2015;12:90‒100.
Weight
Visceral
adiposity
Blood pressure
Arterial
stiffness
Glucose
Insulin
Albuminuria
Uric Acid
Novel
Pathways (?)
LDL-C
HDL-C
Triglycerides
Oxidative
stress
SNS
activity (?)
Link to SGLT2
clinical data
EMPA-REG
OUTCOME®1CANVAS2 CANVAS-R3 CREDENCE4 DECLARE-
TIMI 585
Ertugliflozin
CVOT6
Interventions Empagliflozin/
placebo
Canagliflozin/
placebo
Canagliflozin/
placebo
Canagliflozin/
placebo
Dapagliflozin/
placebo
Ertugliflozin/
placebo
Main inclusion
criteria
Est. vascular
complications
Est. vascular
complications or
≥ 2 CV risk
factors
Est. vascular
complications or
≥ 2 CV risk
factors
Stage 2 or 3 CKD
+
macroalbuminuria
High risk for CV
events
Est. vascular
complications
No. of patients 7034 4339 5700 3627 17,150 3900
Primary
outcome
3P-MACE 3P-MACE Progression of
albuminuria
ESKD,
S-creatinine
doubling,
renal/CV death
3P-MACE 3P-MACE
Key secondary
outcome
4P-MACE Fasting insulin secretion,
progression of albuminuria
Regression of albuminuria,
change in eGFR
4P-MACE + HHF
4P-MACE + HHF +
revascularisation
4P-MACE
Target no.
of events
691 ≥ 420 TBD TBD 1390 TBD
Estimated
median FU
~3 years 6–7 years 3 years ~4 years 4–5 years 5–7 years
Estimated
completion
2015 Apr 2017 2017 2019 2019 2021
Summary of CV outcome trials with SGLT2 inhibitors
25 Adapted from Inzucchi et al. Diabetes Vasc Dis Res 2015;12:90‒100. 1. Zinman et al. Cardiovasc Diabetol 2014;13:102.
2. NCT01032629. 3. NCT01989754. 4. NCT02065791. 5. NCT01730534. 6. NCT01986881.
Link to study
design
Link to study
design
Link to study
design
Link to study
design
Link to study
design
Will report
EASD 2015
SGLT2 Inhibitors – Mechanisms CV Protection
SGLT2 Inhibitors – Renal Protection
Death, Renal
Replacement, Double
SCr
Urinary glucose excretion via SGLT2 inhibition1
31
1. Bakris et al. Kidney Int 2009;75;1272–7.
SGLT2SGLT2
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
Verma and McMurray (2018) Diabetologia DOI 10.1007/s00125-018-4670-7 © G. Oomen 2018
Cardiovascular protection by SGLT2 inhibitors
Diabetes-associated ventricular remodelling
Healthy heart