1_Holistic_Approaches_of_Cardiorenal_Metabolic_for_Treatment_of.pptx

Cardiorenal metabolic management is important to reduce mortality risk

1. HOLISTIC APPROACHES OF CARDIORENAL METABOLIC FOR TREATMENT T2D HOUY PANHA MD, Endocrinologist , Preah Angdoung Hospital Interventional Thyroidologist Lecturer of international programe UHS

2. My Disclosure I have not conflict of interest for this presentation. T he content is based on scientific guidelines and is not influenced by any commercial interests or product promotion.

3. IDF Diabetes Atlas 9 th edition, 2019 Steps survey 2011,2016,2021. prevenance of diabetes type2 , uncommunicable disease (WHO) Cambodian demographic and health survey, CDHS 2021-2022 Global Scenario 463 M Diabetes Population 9.3% Prevalence International Diabetes Federation

4. W hat is Cardio renal metabolic Physiopath

5. Cardiovascular-Kidney-Metabolic Syndrome (CKM) : A systemic disorder involving the interplay between metabolic risk factors (like diabetes and obesity), cardiovascular dysfunction, and chronic kidney disease. These conditions amplify each other, leading to worsened health outcomes, particularly in diabetic patients. What is Cardiorenal Metabolic Syndrome ?

6. Cardiovascular, renal, and metabolic (CVRM) systems are inextricably linked, and there are complex interconnections between CVD, CKD, and diabetes. CKD develops in approximately 40% of people living with diabetes, and is associated with major cardiovascular risk diabetes leads to microvascular damage, which can cause complications that contribute to CKD, such as nephropathy, retinopathy, and neuropathy elevated blood pressure, glucose, serum cholesterol, and body mass index are all common risk factors for CVD, and these factors also increase the risk of CKD and/or diabetes.

7. Risk continuum of T2DM CVD HF CKD Leading to death The Continuum of Cardio-Renal-Metabolic (CRM) Risk Adv Chronic Kidney Dis. 2014 May; 21(3): 273–280 T2DM : Type 2 Diabetic Mellitus; CVD – Cardio Vascular Diseases; HF – Heart Failure CKD – Chronic Kidney Diseases; CV: Cardio Vascular; MI: Myocardial Infarction; LV: Left Ventricular

8. T2D Treatment Goal Keep blood glucose levels near to normal or recommended target range Ensure a good quality life Prevent or delay the progression of micro / macro vascular complications Decrease morbidity and mortality related to DM Rev Esp Cardiol 2002;55(8):845-60 ; OAD: Oral Anti-Diabetics DM – Diabetes Mellitus What are the key beyond Glycemic Control ??? => take care of CRM

9. Clin J Am Soc Nephrol  2017;  12  (12): 2032–2045. - CKD develops in approximately 40% of people living with diabetes, and is associated with major cardiovascular risk - Elevated BP , glucose, cholesterol, and BMI are all common risk factors for CVD, and these factors also increase the risk of CKD and/or diabetes. Connections Between CVD, CKD, and Diabetes

10. Cardio–Metabolic–Renal Interconnections and Therapeutic Options Cardiovasc Diabetol  2023;  22 : 195.

11. W hy we talk about cardio renal metabolic ? T he shift paradigm of T2D treatment from Glucocentric to Hoslistric N ot only glucose and proative approach but take care of CRM effectively reach the treat goal

12. BMJ 2000;321:405-412 UKPDS : UK Prospective Diabetes Study; HbA1c: Glycosylated Hemoglobin UKPDS : Intensive Glycemic Control Is Essential To Improve Micro-Vascular & Macro-Vascular Outcomes Every 1% HbA1c Reduction Death due to Diabetes Heart Attack Microvascular Complication Peripheral Vascular Disorders -21% -14% -37% -43%

13. Current Therapy Focus : Insulin Dependent Limitations Hypoglycemia Weight Gain Beta Cell Fatigue GI Side Effects Reluctance : Injection https://www.ncbi.nlm.nih.gov/books/NBK279141/ ; DPP4i - Dipeptidyl Peptidase-4 Inhibitor; MOA: Mode Of Action; GI: Gastro Intestinal

14. Ability to Lower Glucose Risk of Hypoglycemia Weight Change Effect on ASCVD Effect on CHF Effect on Renal Disease Biguanide High No Modest weight loss Potential Benefit Neutral Neutral Glitazones High No Increase Potential Benefit Potential Benefit Neutral AGI Intermediate No Neutral Neutral Neutral Neutral DPP4i Intermediate No Neutral Potential Benefit Potential Benefit Neutral SUs High Yes Increase Neutral Neutral Neutral Insulin High Yes Increase Neutral Neutral Neutral Effects of Glucose-Lowering Therapies on Cardio-Metabolic Risk Factors https://www.ncbi.nlm.nih.gov/books/NBK279141/ Nov-Dec 2017;60(3):422-434.   doi : 10.1016/j.pcad.2017.09.001 AGI - Alpha- glucosidase inhibitors; DPP4i - Dipeptidyl peptidase-IV (DPP-4) inhibitors; SUs – Sulfonylureas; CHF: Congestive Heart Failure; ASCVD: Athero Sclerotic Cardio Vascular Disease

15. Ability to Lower Glucose Risk of Hypoglycemia Weight Change Effect on ASCVD Effect on CHF Effect on Renal Disease Biguanide High No Modest weight loss Potential Benefit Neutral Neutral Glitazones High No Increase Potential Benefit Potential Benefit Neutral AGI Intermediate No Neutral Neutral Neutral Neutral DPP4i Intermediate No Neutral Potential Benefit Potential Benefit Neutral SUs High Yes Increase Neutral Neutral Neutral Insulin High Yes Increase Neutral Neutral Neutral Effects of Glucose-Lowering Therapies on Cardio-Metabolic Risk Factors https://www.ncbi.nlm.nih.gov/books/NBK279141/ Nov-Dec 2017;60(3):422-434.   doi : 10.1016/j.pcad.2017.09.001 AGI - Alpha- glucosidase inhibitors; DPP4i - Dipeptidyl peptidase-IV (DPP-4) inhibitors; SUs – Sulfonylureas; CHF: Congestive Heart Failure; ASCVD: Athero Sclerotic Cardio Vascular Disease Although several glucose-lowering drugs have been widely used, cardio-renal complications attract considerable attention!!! Therefore, the drugs that provide cardio-renal protection is desired Thus, SGLT2i can be considered

16. Glucose filtration Loop of Henle SGLT2 SGLT1 Glomerulus Proximal tubule Distal tubule Collecting duct No glucose excretion Glucose reabsorption 90% 10% Normal Glucose Homeostasis SGLT2 : Expression & Pharmacological Action Approximately 160g–180g glucose is filtered from the glomerulus & reabsorbed into the blood circulation. No urinary glucose excretion observed in healthy individuals Ni et al. Cardiovasc Diabetol (2020) 19:98 ; SGLT: Sodium–Glucose Co-Transporter

17. Consistent decreases in HbA1c from baseline at week 24 across all dapagliflozin studies 17 10 mg Placebo 10 mg Placebo 10 mg Placebo 10 mg Placebo 10 mg Placebo 10 mg Placebo *p <0.001 compared with placebo * * * * * * 1 Ferrannini E, et al. Diabetes Care 2010;33:2217-24. 2 Bailey CJ, et al. Lancet 2010;375:2223-33. 3 Strojek K, et al. Diabetes Obes Metab 2011;13:928-38. 4 Rosenstock J, et al. 71 st ADA Scientific Sessions , San Diego, 24-28 June, 2011 Abstract 0986-P. 5 Wilding J, et al. Diabetes . 2010;59 ( Suppl 1):A21-A22. Abstract 0078-OR. 6 Henry R, et al. 71 st ADA Scientific Sessions , San Diego, 24-28 June, 2011 Abstract 307-OR. Monotherapy 1 Add-on to Met 2 Add-on to Ins 5 Add-on to Glim 3 8.06 7.92 8.11 8.53 Add-on to Pio 4 8.37 Dapa + Met XR 6 9.05 Baseline HbA1c -0.89 -0.23 -0.84 -0.3 -0.82 -0.13 -0.97 -0.42 -0.9 -0.3 -1.98 -1.44 Primary endpoint for 24-week adjusted  from baseline HbA1c (%)

18. Consistent decreases in fasting plasma glucose (FPG) at week 24 across Dapagliflozin studies 18 1 Ferrannini E, et al. Diabetes Care 2010;33:2217–2224; 2 Bailey CJ, et al. Lancet 2010;375:2223–2233; 3 Wilding J, et al. Diabetes 2010;59 ( Suppl 1):A21–A22 [Abstract 0078-OR]; 6 Rosenstock J, et al. 71 st ADA Scientific Sessions , San Diego, 24–28 June, 2011 [Abstract 0986-P]; Monotherapy 1 Add-on to Met 2 Add-on to Ins 3 Add-on to Pio 4 - 28.8 - 4.1 - 23.4 - 5.94 - 21.7 3.3 - 30 - 6 10 mg Placebo 10 mg Placebo 10 mg Placebo 10 mg Placebo FPG adjusted mean change from baseline mg/ dL mmol /L 0.28 0.00 0.28 0.56 0.83 1.11 1.39 1.67 1.94

19. In DM with Patients not achieving targeted HbA1c Overweight & Obese patients CVD & CKD patients with eGFR>45 in 24ADA , dorp top 25 High risk of hypoglycemia (v/s Insulin / SUs) Curr Opin Endocrinol Diabetes Obes . 2017 Feb; 24(1): 73–79; DM: Diabetes Mellitus; HbA1c: Glycosylated Hemoglobin; CVD: Cardio Vascular Disease CKD: Chronic Kidney Disease; eGFR : Estimated Glumerular Filteration Rate; SUs: Sulfonyl Ureas Dapagliflozin : Ideal Patient Profile Ideal Profile

20. SGLT2 Inhibitors: Do They All Work the Same Way? Drug (dose) Half-life (hours) Oral bioavailability (%) Volume of distribution (L) Plasma protein binding (%) Metabolism and elimination SGLT2 selectivity ( vs SGLT1) Canagliflozin (100–300 mg OD) 10.6–13.1 65 83.5 98 Hepatic conjugated Renal excretion  ~ 250 fold Dapagliflozin (5–10 mg OD) 12.9 78 118 91 Hepatic conjugated Renal excretion  ~ 1200 fold Empagliflozin (10–25 mg OD) 12.4 60 73.8 86.2 Hepatic conjugated Renal excretion  ~ 2500 fold Diabetes Therapy volume 12, pages55–70 (2021); SGLT: Sodium–Glucose Co-Transporter; OD: Once Daily

21. Dapagliflozin v/s Other SGLT2i : Clinical Efficacy SGLT2i: Sodium–glucose co-transporter2 inhibitor; HbA1c; Glycosylated Hemoglobin

22. Kluger et al. Cardiovasc Diabetol (2019) 18:99; SGLT2i: Sodium–Glucose Co-Transporter 2 Inhibitor; hHF : Hospitalization due to Heart failure; CV: Cardio Vascular; Mace: Major Adverse Cardiac Events; ESRD: End Stage Renal Disease Dapagliflozin v/s Other SGLT2i : Cardio-renal Safety Lowest incidences of ESRD progression Lowest incidences of hHF , CV death & MACE

23. Landmark Clinical Trials DAPA – HF DECLARE TIMI-58 DAPA-CKD

24. Pleiotropic effects of SGLT2i

25. Khunti , K. SGLT2 inhibitors in people with and without T2DM.  Nat Rev Endocrinol   17 , 75–76 (2021). https://doi.org/10.1038/s41574-020-00453-2 Potential Mechanism of SGLT2is in Cardiorenal Protection

26. N Engl J Med 381;21 Dapagliflozin : Side Effect Profile

27. Drugs 2019 79:1135-1146; T2DM: Type 2 Diabetes Mellitus; T1DM: Type 1 Diabetes Mellitus; SBP: Systolic Blood Pressure SGLT2 i