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Heart_Failure_in_Diabetes 3 12 25.presentation
- 1. Heart Failure inDiabetes: The Role of SGLT2I Dr. P. Suresh Kumar MD DM Assistant professor of cardiology Chengalpattu medical college
- 2. Learning Objectives • Understanddefinitions and epidemiology of HF in diabetes • Review HF types & pathophysiology • Examine mechanisms linking diabetes to HF • Review evidence for SGLT2 inhibitors and CV outcomes • Summarize major trials and clinical implications
- 3. By 2040, diabetes willbe prevalent in 10% of the world’s population and approx. 50% will be in South East Asia1 Diabetes: The Growing Global Menace 1.IDF DIABETES ATLAS 2019 , 2. Gupta A et.al BMJ Open Diabetes Research and Care 2014;2:e000048. 3. Ferrannini E, Cushman WC. Lancet. 2012;380(9841):601-61 Diabetic 77 Millio n 56.2 Millio n (73%) Diabetic + Hypertension 1 in 2 patients with diabetes also suffer from Hypertension INDIA 4. Lancet Glob Health 2018; 6: e1339–51 Prenissl Jonas et al. PLoSMed 2019;16(5):e1002801:1-18 GLOBAL Diabetes increases risk of incident HF ~2-4 fold.
- 4. Heart Failure andMortality 1/3 will die within 6 months of hospitalisation for heart failure Thereafter 5-10% die every year
- 5. Definition of HeartFailure Clinical syndrome with symptoms and/or signs caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion..
- 6. Symptoms : Typical symptoms breathlessness, fatigue, ankleswelling and/or signs elevated jugular venous pressure, crackles in the lungs, peripheral edema. Structural and/or Functional Cardiac Abnormality: Imaging (e.g., echocardiogram,MRI) Corroborating Evidence Elevated Natriuretic Peptides (BNP or NT-proBNP) and/or Objective Evidence of Congestion (fluid backup) from imaging (X-ray, ultrasound, or invasive hemodynamic measurement).
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- 8. BNP and NTPro BNP Active molecule Byproduct
- 10. Symptoms : Typical symptoms breathlessness, fatigue, ankleswelling and/or signs elevated jugular venous pressure, crackles in the lungs, peripheral edema. Structural and/or Functional Cardiac Abnormality: Imaging (e.g., echocardiogram,MRI) Corroborating Evidence Elevated Natriuretic Peptides (BNP or NT-proBNP) and/or Objective Evidence of Congestion (fluid backup) from imaging (X-ray, ultrasound, or invasive hemodynamic measurement).
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- 17. Left vs RightVentricular Failure • Left ventricular failure: pulmonary congestion, dyspnea. • Right ventricular failure: systemic venous congestion, peripheral edema.
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- 19. Compensatory mechanism ofheart failure
- 20. Pathophysiology Overview Index event Reductionin heart function Compensatory mechanism Try to help initially
- 21. Excessive Compensatory mechanism Deleteriousto heart Index event Initial Compensatory mechanism Neurohormonal activation (RAAS, SNS) Heart Failure
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- 24. HF in Diabetes Diabeticcardiomyopathy (fibrosis, stiffness, diastolic dysfunction) Metabolic dysfunction (lipotoxicity, ) Microvascular dysfunction Accelerated atherosclerosis Inflammation & oxidative stress Autonomic dysfunction Renal dysfunction → RAAS activation
- 25. Mechanism of HeartFailure Due to Diabetes Mellitus Diabetes to HF
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- 28. 2007 Myocardial Infarction (MI):43% increased risk Cardiovascular Death: 64% increased risk TYPE 2 DIABETIC PATIENTS
- 29. Nissen/Wolski Meta-analysis • The "RosiglitazoneCrisis" (The Catalyst) 42 clinical trials
- 30. FDA • 2008 Guidance, •mandating large, long-term • Cardiovascular Outcome Trials (CVOTs) • for all new diabetes drugs.
- 31. Cardiovascular Outcome Trials(CVOTs) Non-Inferiority Demonstrate CV Safety:
- 32. Successfully showed they weresafe (non-inferior). DPP-4 inhibitors
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- 34. • Dapagliflozin • Empagliflozin •Canagliflozin • Ertugliflozin
- 35. 2015 EMPA-REG OUTCOME The UnexpectedFinding Significant reductions in MACE, Massive reduction in hospitalization for heart failure (HHF)
- 36. 2017 CANVAS Program (CANVAS +CANVAS-R) Canagliflozin 2019 DECLARE-TIMI 58 Dapagliflozin
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- 39. Mechanisms of Clinicalbenefit of SGLT2 inhibitors
- 41. Heart Failure withReduced Ejection Fraction (HFrEF), with or without Diabetes 2019 26% reduction primary composite endpoint (CV Death or Worsening HF Event). DAPA-HF Dapagliflozin
- 42. Heart Failure withReduced Ejection Fraction (HFrEF), with or without T2DM. 2020 EMPEROR-Reduced Empagliflozin 25% reduction in the composite endpoint (CV Death or HHF)
- 43. Heart Failure withPreserved Ejection Fraction (HFpEF), with or without T2DM First trial to successfully meet its primary endpoint in HFpEF 2021 EMPEROR-Preserved Empagliflozin
- 44. Heart Failure withPreserved/Mildly Reduced Ejection Fraction (HFpEF/HFmrEF), with or without T2DM 2022 DELIVER Dapagliflozin Confirmed the benefit of SGLT2i in HFpEF/HFmrEF,
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- 47. Modified from: AnkerS, et al. N Engl J Med. 2021;385:1451–1461 and Solomon SD, et al. N Engl J Med. 2022;387:1089–1098. Reprinted with permission from Massachusetts Medical Society. ARR, absolute risk reduction; CI, confidence interval; CV, cardiovascular; HF, heart failure; HHF, hospitalization for heart failure; HR, hazard ratio; LVEF, left ventricular ejection fraction; PY, patient-years; SGLT-2i, sodium-glucose co-transporter-2 inhibitor. 1. Anker S, et al. N Engl J Med. 2021;385:1451–1461; 2. Solomon SD, et al. N Engl J Med. 2022;387:1089–1098. 47 EMPEROR- Preserved1 DELIVER2 Primary outcome: worsening HF or CV death HR=0.79; 95% CI 0.69– 0.90 p<0.001 Months since randomization Cumulative incidence (%) ARR=1.8 % Placebo (n=2991) Event rate = 8.7 per 100 PY Empagliflozin (n=2997) Event rate = 6.9 per 100 PY 25 15 10 20 5 0 0 3 6 12 15 27 36 9 21 24 18 33 30 Residual risk HR=0.82; 95% CI 0.73–0.92 p<0.001 ARR=1.8 % Placebo (n=3132) Event rate = 9.6 per 100 PY Dapagliflozin (n=3131) Event rate = 7.8 per 100 PY Cumulative incidence (%) 30 20 15 5 25 10 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months since randomization Residual risk Primary outcome: CV death or HHF A primary outcome event occurred in 13.8% (n=415) of patients receiving empagliflozin1 A primary outcome event occurred in 16.4% (n=512) of patients receiving dapagliflozin2
- 48. ACEi, angiotensin-converting enzymeinhibitor; ARNI, angiotensin receptor/neprilysin inhibitor; CV, cardiovascular; HF, heart failure; LVEF, left ventricular ejection fraction; SGLT-2i, sodium-glucose co- transporter-2 inhibitor; sMRA, steroidal mineralocorticoid receptor antagonist 1. McDonagh TA, et al. Eur Heart J 2021;42:3599–3726; 2. Heidenreich PA, et al. Circulation 2022;145:e895–e1032 4 proven treatment pillars with CV outcomes Beta blocker ACEi / ARNI sMRA* SGLT-2i HF rEF 1 proven treatment pillar with CV outcomes Finerenone SGLT-2i HFpEF VS
- 49. Major SGLT2i Trials– Compact Comparison Trial (Year) Drug Population Primary outcome (HR) HHF (HR) EMPA-REG (2015) Empagliflozin T2DM + ASCVD MACE: 0.86 (0.74–0.99) HHF: 0.65 CANVAS (2017) Canagliflozin T2DM High-risk MACE: 0.86 (0.75–0.97) HHF: 0.67 DECLARE (2019) Dapagliflozin T2DM broad risk MACE: 0.93 (0.84–1.03) HHF: 0.73 DAPA-HF (2019) Dapagliflozin HFrEF ± T2DM Primary: 0.74 (0.65–0.85) HHF/Worsening HF: 0.70 EMPEROR-Reduced (2020) Empagliflozin HFrEF ± T2DM Primary: 0.75 (0.65–0.86) HHF: 0.69 EMPEROR-Preserved / DELIVER (2022/23) Empagliflozin / Dapagliflozin HFpEF/HFmrEF Primary composite reduced HHF reduced
- 50. References & FurtherReading • Zinman B, et al. EMPA-REG OUTCOME. NEJM 2015. • Neal B, et al. CANVAS Program. NEJM 2017. • Wiviott SD, et al. DECLARE-TIMI 58. NEJM 2019. • McMurray JJV, et al. DAPA-HF. NEJM 2019. • Packer M, et al. EMPEROR-Reduced. NEJM 2020. • Anker SD, et al. EMPEROR-Preserved. NEJM 2022. • Solomon SD, et al. DELIVER. NEJM 2022/2023. • FDA. Guidance for Industry: Diabetes Mellitus — Evaluating CV Risk (2008). • ESC / ACC / AHA Guideline summaries (2021-2024 updates).
- 51. FIVE TARGETS • AngiotensinII, • Neprilysin • Aldosterone, • Norepinephrine, • SGLT2 FOUR PILLARS • ARNI, • Evidence-based beta- blockers, • Mineralocorticoid receptor antagonists, • Evidence-based SGLT2 inhibitors
Editor's Notes
- #25 Mechanism of Heart Failure Due to Diabetes Mellitus The pathophysiological mechanisms between DM and HF are complex and multifactorial. Hyperglycemia, insulin resistance and hyperinsulinemia all seem to provoke and perpetuate the progression of HF, though the exact mechanisms are unclear [28]. Excessive production and accumulation of AGEs in plasma and vascular tissues lead to arterial stiffness and reduced elasticity [29]. Meanwhile, AGE accumulation triggers the production of reactive oxygen species (ROS), leading to myocardial and microcirculatory inflammation, mitochondrial dysfunction and myocardial apoptosis. Additionally, chronic hyperglycemia and insulin resistance may cause direct damage to the myocardium, along with the associated metabolic abnormalities, promoting the development of atherosclerosis and vascular damage. Hyperglycemia contributes to disturbed energy metabolism, inappropriate lipid deposition in extra-adipose tissues (including epicardium) [30] and lipotoxicity, provoking cardiomyocyte damage and triggering myocardial stiffness and ischemia [31]. Eventually, HF leads to renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system activation. When coupled with the typical Western diet, obesity and fatty liver, HF aggravates insulin resistance, and thus begins a vicious cycle [32] (Figure 2). Biomedicines 2024, 12, 1572 4 of 20 studies directly compare the prevalence and incidence of DM in HFrEF and HFpEF patients, in a study of inpatients with HF, the prevalence of DM was approximately 40% in both HFrEF and HFpEF patients [27]. 4.1. Mechanism of Heart Failure Due to Diabetes Mellitus The pathophysiological mechanisms between DM and HF are complex and multifactorial. Hyperglycemia, insulin resistance and hyperinsulinemia all seem to provoke and perpetuate the progression of HF, though the exact mechanisms are unclear [28]. Excessive production and accumulation of AGEs in plasma and vascular tissues lead to arterial stiffness and reduced elasticity [29]. Meanwhile, AGE accumulation triggers the production of reactive oxygen species (ROS), leading to myocardial and microcirculatory inflammation, mitochondrial dysfunction and myocardial apoptosis. Additionally, chronic hyperglycemia and insulin resistance
- #40 Empagliflozin Suppression of the mTORC Pathway – enhanced oxidative phosphorylation- reduced hypertrophy and cardiac stiffness Empagliflozin Regulation of Calcium Within Myocytes- inhibition of CaMK II – slows loss of Ca from SR Empagliflozin Natriuretic and Diuretic Effects Reduces interstitial fluid by 5.2% - hemoconc – increased O2 supply to myocardium the cardiac benefits of empagliflozin are due to improvement in myocardial energetics via switching myocardial fuel metabolism away from glucose to ketone bodies, which ameliorates adverse LV remodeling. Myocardial metabolic remodeling is integral to HF development , with a shift from free fatty acids (FFA) utilization toward glucose consumption in failing hearts. Protects endothelial glycocalx – reduces atherosclerosis