1. SGLT2 INHIBITORS METABOLIC EFFECTS-IN HEALTH AND DISEASE
DR RAVIKANT (M.D)
ASSOCIATE PROFESSOR,
DEPTT OF MEDICINE
AIIMS ,RISHIKESH.

2. GOOD MORNING !

3. Outline
Metabolism in Health and Disease a) Heart b) Kidney c) Other Tissues Role of SGLT-2 inhibitors

5. Energy Metabolism in Health and Disease

6. 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

7. Normal Cardiac Metabolism
95%
FFA 5%
Glucose

8. The healthy heart is able to rapidly switch among energy sources based on workload, hormonal milieu, level of tissue perfusion, and substrate availability.

9. 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.

10. 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

11. Glucose is a more oxygen-efficient fuel compared with FFAs because it has a better ATP yield per oxygen atom consumed (P/O ratio)

12. Why ?

13. 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).

14. 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

15. Options ?

16. 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

17. 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

18. The myocardium is the highest consumer of ketone bodies per unit mass and oxidizes ketone bodies in proportion to their delivery.

19. 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

20. 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
243.6

21. Ultimate Picture

22. 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

23. Kidneys in health and Diabetes

26. 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

27. 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)

32. Cardio-Renal Protection

33. Other Organs

34. Liver Metabolism
In Insulin Deficiency the FFA are Metabolized to produce Ketone Bodies

36. ROLE OF SGLT2 INHIBITORS

39. SGLT2/SGLT1 selectivity
Compound
SGLT2 IC50(nmol/L)
SGLT1 IC50(nmol/L)
SGLT2/SGLT1 selectivity
Highest approved dose (mg)a
Status
Canagliflozin
4.2
663
160
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
Tofogliflozin
6.4
12,000
1,875 20
Ertugliflozin
0.9
1,960
2,200
Phase 3
LX-4211 (sotagliflozin)
1.8 36
400
Completed phase 2

40. BENEFITS AND CLINICAL SAFETY DATA:
A PERSPECTIVE

51. Potential to Grow

52. Thank You