Download SGLT2 Inhibitors

DR RAVIKANT (M.D)
ASSOCIATE PROFESSOR,
DEPTT OF MEDICINE
AIIMS ,RISHIKESH.
GOOD MORNING !
Outline
Metabolism in Health and Disease
a) Heart
b) Kidney
c) Other Tissues
Role of SGLT-2
inhibitors
Energy Metabolism in Health
and Disease
 The human heart
 contracts continuously, with a daily turnover rate of ATP of ;6–35 kg*
 highest oxygen consumption per tissue mass (4.3 mmol/kg/min)

*Opie LH. Heart Physiology: From Cell to Circulation. Philadelphia, Lippincott-Raven Publishers, 1998, p. 43–6
Normal Cardiac Metabolism
95%
FFA
5%
Glucose
 The healthy heart is able to rapidly switch among
energy sources based on workload, hormonal milieu,
level of tissue perfusion, and substrate availability.
 In the fasting state
FFAs are the preferred myocardial fuel for oxidative
metabolism .
In the fed state,
glucose and insulin levels are high,FFA levels are low,
and glucose oxidation is promoted.
During intense exercise, lactate levels increase and
become a predominant fuel.
Ketone bodies contribute significantly to myocardial
energy metabolism only when serum levels are
increased
 Glucose is a more oxygen-efficient fuel compared with
FFAs because it has a better ATP yield per oxygen atom
consumed (P/O ratio)
Why ?
 complete oxidation of one palmitate molecule
generates 105 molecules of ATP and consumes 46
atoms of oxygen (P/O ratio 2.33)
 oxidation of one molecule of glucose generates 31
molecules of ATP and consumes 12 atoms of oxygen
(P/O ratio 2.58).
 Thus, at any level of left ventricular (LV) function,
reliance on FFAs relative to glucose as a metabolic fuel,
as in the setting of insulin resistance and diabetes,
results in a decrease in cardiac efficiency and an
increased propensity for HF
Options ?
KETONES AS AN ALTERNATIVE
MYOCARDIAL FUEL SOURCE
 Unfortunately, the words
ketone bodies are
associated with diabetic
ketoacidosis and are
regarded unfavorably in
the clinical setting
 In reality, ketone bodies (3-bhydroxybutyrate) (BHOB)
have served as an alternative fuel for 2 billion years and
have played a critical role in human survival during
periods of starvation,providing fat-derived calories to
the brain, heart,kidneys,and other vital tissues*
* Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological
conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism.
Prostaglandins Leukot Essent Fatty Acids 2004;70:309–319
 The myocardium is the
highest consumer of ketone
bodies per unit mass and
oxidizes ketone bodies in
proportion to their delivery.
In Failing Heart
 In T2DM with HF, there is
dysregulated fatty acid
oxidation and impaired
glucose uptake/oxidation,
which lead to myocardial
dysfunction. In this setting
of restricted fuel selection
and low energetic reserve,
ketone bodies are a super
fuel , producing ATP more
efficiently than glucose or
FFAs with a P/O ratio of
2.50
substrate
p/o
Energy liberated
Kcal/mol 2 carbon atom
Glucose
2.58
223.6
Pyruvate
2.50
185.7
Palmitate
2.33
298
BHOB
2.50
243.6
Ultimate Picture
Elevated Ketone Bodies With SGLT2
Inhibitors and in HF
 It is well documented that ketone bodies are elevated
in patients treated with SGLT2 inhibitor
 In Japanese study; 1,300subjects,fastingketones were >1
mmol/L in 12–20% of patients treated with 100–200
mg canagliflozin daily for 52 weeks*
*Inagaki N, Goda M, Yokota S, Maruyama N, Iijima H. Safety and efficacy of canagliflozin in
Japanesepatientswithtype2diabetesmellitus: post hoc subgroup analyses according to body mass
index in a 52-week open-label study. Expert Opin Pharmacother 2015;16:1577–1591
Kidneys in health and Diabetes
FUEL METABOLISM IN THE NONDIABETIC KIDNEY
 The kidney is highly active metabolically, with 80% of
energy consumption fueling sodium reabsorption
through the Na+/K+ ATPase pump
 To meet energy requirements and sustain the GFR, the
kidney has a high blood flow (25% of the cardiac
output). Consequently, renal oxygen consumption
(QO2) per gram of tissue is second only to the heart
(2.7vs. 4.3 mmol/kg/min, respectively)
Cardio-Renal Protection
Other Organs
Liver Metabolism
 In Insulin Deficiency the
FFA are Metabolized to
produce Ketone Bodies
ROLE OF SGLT2 INHIBITORS
Compound
Canagliflozin
SGLT2
IC50(nmol/L)
4.2
SGLT1
IC50(nmol/L)
663
SGLT2/SGLT
1 selectivity
160
Highest
approved
dose (mg)a
Status
300
Approved in
U.S., EU,
Japan
Dapagliflozin
1.2
1,400
1,200
10
Approved in
U.S., EU,
Japan, others
Empagliflozin
3.1
8,300
2,700
25
Approved in
U.S., EU
Ipragliflozin
5.3
3,000
570
50
Approved in
Japan
Luseogliflozin
2.3
3,990
1,770
5
Approved in
Japan
Tofogliflozin
6.4
12,000
1,875
20
Approved in
Japan
Ertugliflozin
0.9
1,960
2,200
25
Phase 3
LX-4211
(sotagliflozin)
1.8
36
20
400
Completed
phase 2
BENEFITS AND CLINICAL
SAFETY DATA:
A PERSPECTIVE
Potential to Grow
Thank You