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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