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SGLT2 inhibitors
- 1. SGLT-2 Inhibitors The GameChanger Ahmed ElBorae, MSc Assistant lecturer of Cardiology, Cairo University Specialist of Cardiology, Aswan Heart Centre
- 2. Agenda • Mechanism ofaction • Cardiovascular prevention • Heart failure treatment • Renal protection • Daily practice guidance
- 3. 6 types ofSGLT Bhargavan, et al. BMH Medical Journal 2015;2(4):97-101 Brain Liver Thyroid Muscles ,Glucose sensor
- 4. SGLT-2 Function • Effect↓↓ with low glucose level • Low risk of hypoglycemia Martin et al. Nature review, Cardiology 2020. doi.org/10.1038/s41569-020-0406-8 Normally near 100% of filtrated Glucose is reabsorbed No Glucose in urine (Renal threshold 180 mg/dl) With full SGLT-2 blockage Only 60% excreted Due to Increased SGLT-1 action SGLT-2 responsible for reabsorption of 5% of filtrated Na in non-DM, and 15% in DM (Upregulation)
- 5. SGLT inhibitors evolution •Phlorizin in 1980s, non-selective (SGLT-1i and SGLT-2i), poor oral bioavailability • Currently, four members are licensed by FDA/EMA: (Dapagliflozin, Empagliflozin, Canagliflozin, and Ertugliflozin) • Five other>Three (ipragliflozin, luseogliflozin and tofogliflozin) approved in Japan,(remogliflozin) in India and (Sotagliflozin) in Europe 10 family members
- 6. Cardiovascular benefits -Not glycemiccontrol related -Occurred early after initiation Same CV benefits in non diabetics Bhargavan, et al. BMH Medical Journal 2015;2(4):97-101
- 7. SGLT-2 inhibitors mechanismof action • ↓Sympathetic tone ? • ↓ oxidative stress ? (↑ autophagy, Lysosomal activity) • Anti-Fibrotic? (↓TGF-B,Fibroblast,Collagen I,III in rats) • Anti-Inflammatory? (↓CRP-TNF-IL-6 ,NLRP3 in rats) • ↓ Ischemia/reperfusion injury “Rat” (↓ calmodulin kinase II activity) Verma et al. JAMA cardiology. 2017. n 250 kcal/day ↓4/2 mmHg 300ml/day 1st then decline ↑ 7% EPO ↓ A/C ratio by 15mg/g ↓TNF Epicard. ↑K+ channels ↑protein kinase G ↓reabsorption ↓ cellular Ca,Na 30%↑ urinary Na Mainly interstitial
- 9. DAPA-LVH (Dapagliflozin reduced LVmass in T2DM+LVH+controlled BP) At 12 months CMR 66 patients
- 10. EMPA-TROPISM Empagliflozin reduced LVvolumes by CMR in HFrEF +No DM At 6 months 84 patients
- 11. EMPA-TROPISM Empagliflozin improved LVEF,LVmass,PVO2, and 6-min walk
- 12. SUGAR-DM-HF Empagliflozin improved LVvolumes in HFrEF+T2DM/Pre-DM 105 patients At 9 months
- 13. Rare, 0.4% innon DM 5% in males, 10% in females
- 14. Agenda • Mechanism ofaction • Cardiovascular prevention • Heart failure treatment • Renal protection • Daily practice guidance
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- 16. The only class >HF+CV benefits Diabetes Care 2020;43(Suppl. 1):S98–S110 | https://doi.org/10.2337/dc20-S009 2020
- 17. Martin et al.Nature review, Cardiology 2020.
- 18. Established CV diseaseVs. Having Risk factors only Only patients with established CV disease showed mortality benefit Both showed reduction of HFH benefit Zelniker et al. Lancet 2019; 393: 31–39
- 19. HFH benefit isconsistent irrespective of previous history of heart failure Zelniker et al. Lancet 2019; 393: 31–39
- 20. Survival and HFhospitalization benefits independent of baseline HBA1C or glycemic control Inzucchi,et al.Circulation. 2018;138:1904–1907. Post-HOC analysis (EMPAREG trial)
- 21. Post-HOC analysis (DECLARETIMI trial) • Survival benefits in HFrEF • HF hospitalization benefits Regardless EF Eri T Kato, et al.Circulation. 2019;139:2528–2536.
- 22. ↓ 35% ↓ 33% ↓27% ↓ 30% Butler J,et al.European Heart Journal (2020) 41, 3398–3401
- 23. Agenda • Mechanism ofaction • Cardiovascular prevention • Heart failure treatment • Renal protection • Daily practice guidance
- 25. 263 patients withHFrEF (EF≤40%) +↑BNP+NYHA II-III and eGFR ≥30 38% non-DM Outcome: 12 Weeks mean NT-pro BNP, ≥ 5 ↑points in Kansas CCQ, ≥ 20% ↓ NT-pro BNP Significant improvement in Kansas CCQ, ≥ 20% ↓ NT-pro BNP Regardless DM status
- 26. Butler J,et al.EuropeanHeart Journal (2020) 41, 3398–3401
- 27. Baseline characteristics ARNI 20%10% Butler J,et al.European Heart Journal (2020) 41, 3398–3401
- 28. ↓ 25% ↓ 30% ↓18% Butler J,et al.European Heart Journal (2020) 41, 3398–3401
- 29. Zelniker et al.Lancet 2019; 393: 31–39 Meta-analysis of both land mark trials extended survival benefit
- 30. Zelniker et al.Lancet 2019; 393: 31–39 Meta-analysis of both land mark trials regardless DM status or HBA1c level
- 31.
- 32. Regardless the evidenceof recent volume overload
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- 34. Voors A A,et al.European Journal of Heart Failure (2020) 22, 713–722 80 patients with acute HF (RCT,Empagliflozin 10mg vs. Placebo) 67% non-DM Outcome: 1ry: (VAS) dyspnea score, diuretic response(Weight!), change NT-proBNP, and length of stay 2ry: (1)composite of in-hospital worsening HF, re-hospitalization for HF or death at 60 days (2) UOP • No Significant change in dyspnea, weight, NT-proBNP or length of stay • Significant ↓HF worsening, HFH, and death at 60 days (Not Powered)
- 35. Significant ↑ inCumulative UOP and more negative balance
- 36. SOLOIST-WHF trial (Sotagliflozin inrecently worsened HF +DM) 1222 patients ↓ 33% in composite 1ry endpoint (Cardiac death-HFH-Urgent HF visits) Mainly driven by HFH/Visits but not death B.Pitt et al. NEJM 2021
- 37. Benefit is persistentregardless EF% Limitations: -Small number of HFpEF -Not powered -Premature termination (Fund)
- 38. Agenda • Mechanism ofaction • Cardiovascular prevention • Heart failure treatment • Renal protection • Daily practice guidance
- 39. Normally initial dip5 ml/min./mm2 Effect on eGFR (EMPEROR-Reduced trial) Zannad et al.circulation. 2021 Jan 26;143(4):310-321
- 40. Reduction of thecomposite of worsening of renal function, end-stage renal disease, or renal death independent of baseline eGFR Zelniker et al. Lancet 2019; 393: 31–39 The lower the baseline eGFR, the lower hypoglycemic effect due to lower filtrated drug, yet with persistent CV/Renal benefits
- 41. 34 % ↓composite of doubling of creatinine, ESKD or renal death ↓ 30% Perkovik v, et al.nejm.2019, 380;24
- 42. 4304 patients witheGFR(25-75)+A/C ≥200 32% non-DM Outcome:(Sustained ↓eGFR 50%,ESKD, cardiac/ renal death) ↓ 39% ↓ 29% Heerspink,et al.NEJM 2020.
- 44. SCORED trial D.L Bhatt,et al.NEJM.2021
- 45. Agenda • Mechanism ofaction • Cardiovascular prevention • Heart failure treatment • Renal protection • Daily practice guidance
- 46.
- 47. The CHAMP-HF Registry Greene,et al. JACC.2018:351-66 Current gap in GDMT • Need uptitration 3185 HFrEF patients 150 US centers % of patients reaching the target dose • ARNI (14%) • ACEI/ARB (17%) • Beta-blocker (28%) • MRA therapy (77%) • ACEI+BB+MRA (1%)
- 48. Advantages of SGLT-2i •Once daily • No need for up titration • Few side effects Bassi N S, et al. JAMA Cardiology 2020. Quadruple therapy (ARNI+BB+MRA-SGLT-2i) Number needed to treat to prevent one death= 3.9
- 49. Ad-hoc analysis DAPA-HF> Consistent benefit regardless HF background therapy John J.V. McMurray,et al. ESC 2020
- 50. Cumulative evidence (ARNI-MRA-SGLT2i) Crossanalysis of (EMPHASIS+PARADIGM-HF-DAPA-HF) Add 8.3 years event free (+6.3 yrs survival) aged 55 years Add 2.7 years event free (+1.4 yrs survival) aged 80 years Scott D Solomon,et al. Lancet 2020
- 51. “The Fantastic four” JohannBauersachs.ESC2021.
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- 56. Cardiac prevention inType 2 DM
- 57. 2019 2020 Diabetes Care 2020;43(Suppl.1):S98–S110 2019
- 58. Ongoing Trials Martin etal. Nature review, Cardiology 2020. doi.org/10.1038/s41569-020-0406-8
- 59. Take home message •SGLT-2i showed significant survival and HF hospitalization benefits in patients with HFrEF ≥ NYHA II with elevated BNP and eGFR ≥ (20-30 ml/min./1.73mm2) • SGLT-2i benefits is persistent regardless DM status or background HF GDMT • SGLT2i showed significant reduction of cardiac death in patients with type 2 DM and established CV disease • SGLT2i showed significant reduction of HF hospitalization in patients with type 2 DM and risk factors for CV disease • SGLT2i showed significant reduction of renal death or progression to ESKD in patients with type 2 DM and macro albuminuria (EMPAREG-DECLARE TIMI-CANVAS) (EMPEROR REDUCED-DAPA HF) (CREDENCE-DAPA CKD) (EMPAREG-DECLARE TIMI-CANVAS)
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