Management of cardio renal metabolic complications

Management of cardiology renal metabolic complications

1. Management of cardio-renal- metabolic (CaReMe) conditions: Pleotropic benefits of Dapagliflozin Dr. Geetesh Manik HOD and Director Cardiology ASIAN Vivekanand Hospital, Moradabad

2. Cardio- Renal - Metabolic interaction in T2DM - A snapshot 3 Adapted from:Cernea S. Heart failure and chronic kidney disease in type 2 diabetes. Journal of Interdisciplinary Medicine. 2016 Dec 1;1(3):252- 8.

3. 4 50 45 40 35 30 25 20 15 10 5 Prevalence (%) Diabetes as a co- morbidity in HF - Prevalence in HFrEF trials HF trials

4. CV mortality in T2DM A total of 153 403 patients with newly diagnosed T2D were followed for a median of 9.7 years; effect of HF development on prognosis compared with other cardiovascular (IHD, PAD, stroke) or renal ( CKD) diagnoses in patients with T2D was examined. HF development , at any year since T2D diagnosis , was associated with the highest 5- year absolute and relative risk of death , and decrease in lifespan within 5 years, when compared with development of other cardiovascular or renal diagnoses Zareini et al; Heart Failure and Diabetes Mellitus; Circ Cardiovasc Qual Outcomes. 2020

5. Prevalence of kidney disease in Diabetes 6 diabetic kidney disease ~40% of diabetics develop Diabetes is the leading cause of CKD globally Tuttle KR et.al. American Journal of Kidney Diseases. 2020;77(1):94- 109.

6. Pathophysiology of Diabetic Kidney disease 7 Adapted from: Lin YC et,al. Update of pathophysiology and management of diabetic kidney disease. Journal of the Formosan Medical Association. 2018 Aug 1;117(8):662- 75.

7. HF and CKD as co- morbidities : Prevalence & Prognosis 8 ~63 % HF patients have renal impairment - Every 10 ml/min eGFR decrease leads to increase in mortality by 7% in HF patients 3 times more risk of HF in patients of CKD as compared to non CKD individuals Shiba N et.al. Chronic kidney disease and heart failure— Bidirectional close link and common therapeutic goal. Journal of cardiology. 2011 Jan 1;57(1):8- 17. Karnib HH et.al. Diabetes research and clinical practice. 2010 Sep 1;89(3):201- 8. Segall L, Nistor I, Covic A. Heart failure in patients with chronic kidney disease: a systematic integrative review. BioMed research international. 2014 Jan 1;2014.

8. Update on Guidelines

9. ADA 2022 Adapted from: American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes- 2022. Diabetes Care 2022;45(Suppl. 1):S125–S143 | https://doi.org/10.2337/dc22- S009 Patient Profile based approach for the management of T2DM

10. AACE – ACE 2020 Guidelines

11. ESC- EASD 2019 Guidelines

12. Management of Cardio- Renal- Metabolic Conditions: Role of Dapagliflozin

13. 14 Renal-protective pathways with SGLT2 inhibitors Giorgino F et.al. Cardiovascular Diabetology. 2020 Dec;19(1):1- 9.

14. SGLT2i: Mechanisms for Improving Cardio- Renal- Metabolic outcomes 15 Khunti K. Nature Reviews Endocrinology. 2020 Dec 8:1- 2.

15. Pleiotropic benefits with SGLT2i 01 02 03 04 05 06 07 BP Reduction Treatment of CKD Glycemic control ASCVD Risk Reduction Weight reduction No risk of Hypoglycemia Treatment of HFrEF & hHF Risk Reduction 16

16. Management of Cardio- Renal- Metabolic Conditions: Insights from Recent trials

17. 1. Inzucchi S et al. Diab Vasc Dis Res 2015;12:90; 2. Heise T et al. Clin Ther 2016;38:2265; 3. Vallon V & Thomson SC. Diabetologia 2017;60:215; 4. Heerspink HJ et al. Circulation 2016;134:752; 5. Verma S et al. Circulation 2019; doi:10.1161/CIRCULATIONAHA.119.042375 18 SGLT2 inhibition modifies several CV and HF risk factors 1 SGLT2 inhibition 2 Mechanism 2 Observed effects 3–5 Glucose excretion Natriuresis Diuresis Cardiac function Preload Afterload Cardiometabolic efficiency Kidney function Weight Blood pressure Left ventricular mass HbA1c

18. 19 Dapagliflozin Placebo Metabolic benefits with Dapagliflozin *Statistically significant versus placebo using Dunnett’s correction (p<0.0001); † Statistically significant versus placebo (p<0.0001); ‡ Statistically significant versus placebo (p<0.001). OAD, oral antidiabetic drug. 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. Jabbour SA, et al. Diabetes Care 2014; 37 :740–50; 5. Wilding JPH , et al. Ann Intern Med 2012; 156 :405–15. Consistent reductions in HbA 1c as monotherapy and as add-on to commonly prescribed treatments Metabolic benefits

19. Dapagliflozin - Durable Glycemic Control : Significant HbA 1c reductions sustained over 2 years 1 20 Dapagliflozin is not indicated for the management of obesity. 3 Weight change was a secondary endpoint in clinical trials. 2,3 A Phase III, multicentre, randomised, double- blind, placebo- controlled, parallel- group, 24-week clinical study with a 78-week, double- blind extension in adult patients with Type 2 diabetes who had inadequate glycaemic control (HbA 1c ≥7% and ≤10%) on metformin alone. Primary endpoint: HbA 1c reduction at 24 weeks. Data are mean change from baseline after adjustment for baseline value. Data after rescue are excluded. Analyses were obtained by longitudinal repeated- measures analyses. CI, confidence interval. 1. Bailey CJ, et al. BMC Med 2013; 11 :43; 2. Bailey CJ, et al. Lancet 2010; 375 :2223–33; 3. Dapagliflozin. Summary of product characteristics, 2014. Metabolic benefits

20. 21 Dapagliflozin is not indicated for the management of obesity. 3 Weight change was a secondary endpoint in clinical trials. 2,3 A Phase III, multicentre, randomised, double- blind, placebo- controlled, parallel- group, 24- week clinical study with a 78-week, double- blind extension in adult patients with Type 2 diabetes who had inadequate glycaemic control (HbA 1c ≥7% and ≤10%) on metformin alone. Primary endpoint: HbA 1c reduction at 24 weeks. 1,2 Data are mean change from baseline after adjustment for baseline value. Data after rescue are excluded. Analyses were obtained by longitudinal repeated- measures analyses. 1. Bailey CJ, et al. BMC Med 2013; 11 :43; 2. Bailey CJ, et al. Lancet 2010; 375 :2223–33; 3. Dapagliflozin. Summary of product characteristics, 2014. Dapagliflozin - sustained weight loss over 2 years 1 Metabolic benefits

21. 22 SGLT2 Inhibitor CVOT Study Cohorts (All Patients with T2DM) CAD, coronary artery disease; CVD, cardiovascular disease; PAD, peripheral artery disease. 1. Zinman B et al. N Engl J Med. 2015;373:2117-28. 2. Neal B et al. N Engl J Med. 2017;377:644-657. 3. Wiviott SD et al. Am Heart J. 2018;200:83- 89. EMPA- REG OUTCOME CANVAS Program DECLARE- TIMI 58 100% 2 o Prevention 34% 1 o Prevention ~60% 1 o Prevention Risk Factors without established CVD 66% 2 o Prevention ~40% CAD CVD PAD 2 o Prevention

22. 23 Renal- related Composite Outcomes Doubling of the serum creatinine level, initiation of renal- replacement therapy, or death from renal disease EMPA- REG OUTCOME 1 40% reduction in eGFR, renal- replacement therapy (dialysis or transplantation), or death from renal causes CANVAS Program 2 0.60 (0.47-0.77) Sustained ≥40% decrease in eGFR to <60 mL/min/1.73 m 2 and/or end-stage renal disease and/or renal death DECLARE-TIMI 58 3 0.53 (0.43- 0.66) p <0·0001 HR (95% CI) 0.54 (0.40-0.75) SGLT2i: Renal Outcomes in CVOTs Dapagliflozin showed significant renal benefits in T2DM patients † Intention-to- treat analysis set, 95.8% CI. AE, adverse event; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio; SGLT2, sodium-glucose cotransporter 2. 1. Wanner C et al. N Engl J Med 2016;374:323-334; 2. Neal B et al. N Engl J Med 2017;377:644-657; 3. Wiviott SD et al. N Engl J Med 2019;380:347- 357. Mosenzon O et.al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE–TIMI 58 randomised trial. The lancet Diabetes & endocrinology. 2019 Aug 1;7(8):606- 17. Renal benefits

23. CVOT Meta-analysis: Renal outcomes by presence of ASCVD Zelniker TA, Wiviott SD, Raz I, et al. Lancet. 2019 Jan 5;393(10166):31-39. Zelniker TA et al. SGLT2 Inhibitors for Primary and Secondary Prevention of Cardiovascular and Renal O 2 u 4 tcomes in Type 2 Diabetes: A Systematic Review and Meta- analysis of Cardiovascular Outcome Trials. Dapagliflozin provides significant reno- protection in T2DM patients with both eCVD and multiple cardiovascular risk factors p<0·0001 P=0.05 Renal benefits

24. DECLARE- TIMI 58 Trial: Effect of Dapagliflozin on Risk for Fast Decline in eGFR 25 Dapagliflozin reduced the risk for Fast Decline in eGFR in a broad population of patients with T2D and either established or increased risk for CVD , but relatively preserved renal function, irrespective of patients’ baseline characteristics. ADA 2020 303-OR - Effect of Dapagliflozin on Risk for Fast Decline in EGFR: Analyses from the DECLARE-TIMI 58 Trial accessed from : https://plan.core- apps.com/tristar_ada20/abstract/f2ba949f-36f3-4dea-9572- ae5bd401af2c Renal benefits

25. DAPA- HF: Primary composite outcome Placebo Dapagliflozin CV Death/HF hospitalization/Urgent HF visit Diabetes Dapagliflozin Placebo No Diabetes P interaction 0.80 HR 0.73 (0.60,0.88) 27% RRR Placebo Dapagliflozin HR 0.75 (0.63,0.90) 25% RRR 1. McMurray JJV et al. Article and supplementary appendix. Eur J Heart Fail. 2019;21:665- 675; 2. McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France; 3. Study NCT03036124. ClinicalTrials.gov website. Accessed August 19, 2019. 4. McMurray JJV et al. Eur J Heart Fail . 2019;doi: 10.1002/ejhf.1548. Accessed July 16, 2019.

26. DAPA- CKD: Dapagliflozin in Patients With CKD (with or without T2DM) 1,2 a ESKD defined as the need for maintenance dialysis (peritoneal or hemodialysis) for at least 28 days and renal transplantation or sustained eGFR <15mL/min/1.73m 2 for at least 28 days. ACEi = angiotensin- converting enzyme inhibitor; ANCA = anti-neutrophil cytoplasmic antibody; ARB = angiotensin- receptor blocker; CKD = chronic kidney disease; CV = cardiovascular; eGFR = estimated glomerular filtration rate; ESKD = end- stage kidney disease; hHF = hospitalization for heart failure; T1D = type 1 diabetes; T2D = type 2 diabetes; UACR = urinary albumin-to- creatinine ratio. 1. Heerspink HJL et al. Nephrol Dial Transplant . 2020;35:274–282; 2. Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 - September 1, 2020. Composite of sustained ≥50% eGFR decline, ESKD, or renal death Composite of CV death or hHF All- cause mortality Secondary Outcomes Dapagliflozin 10 mg + standard of care Placebo + standard of care 1:1 Double-blind End Points Composite of sustained ≥50% eGFR decline, ESKD a , renal or CV death Primary Outcome 4304 Randomized Median follow- up 2.4 years To assess whether treatment with dapagliflozin, compared with placebo, reduced the risk of renal and CV events in patients with CKD with or without T2D, and who were receiving standard of care including a maximum tolerated dose of an ACEi or ARB Objective Key Inclusion Criteria ≥18 years of age eGFR ≥25 to ≤75 mL/min/1.73m 2 UACR ≥200 to ≤5000 mg/g Stable max tolerated dose of ACEi/ARB for ≥4 weeks With and without T2D Key Exclusion Criteria T1D Polycystic kidney disease, lupus nephritis, ANCA- associated vasculitis Immunosuppressive therapy ≤6 months prior to enrollment

27. 28 DAPA- CKD: Results T2DM Dapagliflozin showed significant benefit irrespective of T2DM status Wheeler DC et.al. The Lancet Diabetes & Endocrinology. 2021 Jan;9(1):22- 31. Secondary (renal specific) Composite Outcome: Sustained ≥50% eGFR Decline, ESKD, or Renal Death 43% RRR With dapagliflozin in Diabetics RRR= Relative Risk Reduction vs Placebo Renal benefits

28. Deliver Trial: in a nutshell Clinical Trials - Hot Lines at ESC Congress [Internet]. Escardio.org. 2018 [cited 2022 Aug 30]. Available from: https://www.escardio.org/Congresses-&- Events/ESC- Congress/Scientific-sessions/clinical-trials-hot-lines NNT = 32

29. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure with mildly reduced and preserved ejection fraction 2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure - DOI: 10.1016/j.cardfail.2022.02.010 In patients with symptomatic chronic HFpEF & HFmrEF, SGLT2i are recommended to reduce hospitalization for HF and cardiovascular mortality, irrespective of the presence of type 2 diabetes

30. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure 2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure - DOI: 10.1016/j.cardfail.2022.02.010 In patients with symptomatic chronic HFrEF, SGLT2i are recommended to reduce hospitalization for HF and cardiovascular mortality, irrespective of the presence of type 2 diabetes

31. Summary Diabetes is a known factor that increases the risk of HF and CKD Co- morbidities associated with Diabetes – like Hypertension, Dyslipidemia etc further increase the risk of HF and CKD in diabetes patients Dapagliflozin helps in preventing HF in Diabetes patients with established ASCVD or with multiple CV risk factors Dapagliflozin has reno protective effect in T2DM patients (DECLARE –TIMI & DAPA CKD) Dapagliflozin helps reduce risk of adverse Cardio- renal outcomes in T2DM patients 32

32. THANK YOU.. Questions?