The cardiorenal connection & diabetes: Exploring opportunities for intervention Dr. Maria Rosa Costanzo, MD Naperville, Illinois, USA June 7, 2020 - Virtual ERA-EDTA
The Cardiorenal Connection & Dia iabetes: Exploring Opportunities for In Interv rvention Maria Rosa Costanzo, M.D., F.A.H.A., F.A.C.C., F.E.S.C. Medical Director, Heart Failure Research, Advocate Heart Institute Medical Director, Edward Hospital Center for Advanced Heart Failure 801 South Washington Street Naperville, Illinois, U.S.A
Distinguishing Features of f SGL2 In Inhibitors • Cause weight loss by exporting calories from the body to the urine • Reduce BP commensurate to their natriuretic effect • Are uricosuric • Inhibition of the tubular urate transporter URAT1 • Tubular fluid glucose trans-stimulate uric acid secretion by the facilitative glucose transporter GLUT9 • Do not cause hypoglycemia because glycosuric effect disappears when blood glucose levels decline below 70mg/dL, as a result of transport capacity residual in SGLT1 and because the drugs leave metabolic counter-regulation intact • Reversibly lessen GFR (i.e. reduce hyperfiltration)by activating TGF
Anticipated Effects of SGLT2 In Inhibitors on Clinical variables in T2DM Patients Due to Decreased BV, Reduced Arterial Stiffness, Improved Endothelial Function David Z. Cherney et al. J Am Coll Cardiol 2019;74:2511-2524
Selected Physiological Mechanisms Associated With Cardiovascular and Renal Protection With SGLT2 Inhibitors David Z. Cherney et al. J Am Coll Cardiol 2019;74:2511-2524
SGLT2 Mechanism in in th the Early Proximal Tubule ✓ Normal daily GF contains 1 mol (180 mg) glucose. ✓ If all excreted in the urine, loss of energy equivalent to 30% of body’s caloric expenditure. ✓ SGLT1 and 2 can reabsorb 2.5 mol glucose/day. ✓ SGLT1 reabsorbs 2 Na per glucose; SGLT2 1 Na per glucose. ✓ SGLT2 reabsorbs 25% of Na linked to bicarbonate reabsorption. ✓ If filtered glucose rises to transport max. then the amount of Na that passes through SGLT increases to 19 mmol/L or 80% of Na directly linked to bicarbonate. ✓ Na reabsorption draws water, increasing Cl Thomson SC, Vallon V. concentration and further increasing NaCl Am J Cardiol 2019;124:S28 − S35 reabsorption.
Renal Outcomes in in SGLT2 In Inhib ibit itors and in in Captopril l Tria ials Thomson SC, Vallon V. Am J Cardiol 2019;124:S28 − S35
Similarity of eGFR Outcomes in SGLT2 Inhibitor Clinical Trials Thomson SC, Vallon V. Am J Cardiol 2019;124:S28 − S35
Immediate Effects of Phlorizin Delivered to Bowman’s Space on Macula De Densa De Deli livery ry of of Na Na, Cl, l, Flu Fluid id Vol olume, an and SNGFR Measured Do Downstream of of th the Mac acula la De Densa to Allo llow TGF to Operate. Early Distal Tubule Flow Rate Determined by Distal Tubular Collection Thomson SC, Vallon V. Am J Cardiol 2019;124:S28 − S35
Acu cute an and Chronic Effects of of SG SGLT2 Blo lockade with ith Da Dapagli liflozin on on Tubular Reabsorption in in a a Rodent Mod odel of of Earl arly Di Diabetes Intact TGF Attenuated Chronic Response due to Compensatory Reabsorption Thomson SC, Vallon V. in the Loop of Henle Am J Cardiol 2019;124:S28 − S35
Media ian Change in in 24-h h Systolic ic BP and Media ian % Change in in Pla lasma Volume and Red Cell ll Mass Lambers Heerspink HJ et al. Diabetes Obes Metab 2013;15: 853-63
Mechanis isms of In Interstit itial l and In Intravascular Volume Exp xpansion in in HF Miller WL. Circ Heart Fail. 2016;9: e002922.
Changes in Skin Sodium Content aft fter 6 Week Treatment with SGLT2 In Inhibitors Karg MV et al. Cardiovasc Diabetol 2018; 17:
SGLT2 and Sodium-Hydrogen Exchange ➢ Co-localization and positive interference between SGLT2 and sodium-hydrogen exchanger (NHE) ➢ Inhibition of SGLT2 suppresses the activity of NHE3 ➢ Knocking out tubular NHE3 reduces expression of SGLT2 and the natriuretic effect of SGLT2 blockade. ➢ The coupling may facilitate the GTB of sodium, glucose, and bicarbonate when GFR is increasing. ➢ Acid-base balance and glucose metabolism are already coupled through phosphoenolpyruvate carboxykinase ➢ (PEPCK), a key enzyme for both gluconeogenesis and the renal compensatory response for systemic acidosis. ➢ Blood glucose will rise whenever tubular PEPCK is stimulated by acidosis and systemic pH will rise when PEPCK is stimulated to perform gluconeogenesis. ➢ This confounding could be mitigated by having SGLT2 and NHE3 change in parallel because increasing SGLT2 to raise cell glucose above its equilibrium concentration would suppress ➢ PEPCK and increasing NHE3 expression would sustain ammonia secretion, thereby allowing the proximal tubule to perform its function as a regulator of systemic pH with less reliance on PEPCK ➢ empagliflozin suppresses NHE1 in cardiac myocytes, which do not express SGLT2
Metabolic and Macula Densa Effects ❖ SGLT2 inhibitors are ketogenic and thereby improve cardiac function (the heart requires less oxygen when generating ATP from ketones. SGLT2 could also benefit the diabetic kidney by this same mechanism, effectively reducing regional hypoxia. ❖ Blocking the macula densa nitric oxide synthase 1(NOS1) eliminates hyperfiltration in diabetic rats while having minimal impact on GFR in nondiabetic animals. ❖ Macula densa cells express SGLT1 and activating SGLT1 in MD triggers NOS1 activity. ❖ New studies show knockout of SGLT1 prevents diabetes-induced upregulation of NOS1 in the macula densa and mitigates glomerular hyperfiltration. ❖ Absence of SGLT1 also attenuates upregulation of macula densa NOS1 expression in response to SGLT2 inhibition in non-diabetic mice. ❖ Effects of SGLT1 and SGLT2 inhibition on diabetic glomerular hyperfiltration are additive.
Empaglifl flozin In Increases Cardiac Energy Production in Diabetes
Areas of f Overlap for Clinical Trials wit ith SGLT2 in in Pati tients with CKD
All ll-Cause Mortali lity, CV Events, an and Renal l Outcomes in in CVOTs of of SG SGLT-2 In Inhibit itors ➢ Reduction in albuminuria and hard renal outcomes: ➢ Over a wide range of baseline HgbA1c ➢ Across albuminuria ranges ➢ With and without baseline renal impairment ➢ In DECLARE renal benefit occurred even though renal risk was low at baseline (eGFR 85 ml/min/1.73m 2 ) David Z. Cherney et al. J Am Coll Cardiol 2019;74:2511-2524
All ll-Cause Mortality, CV Events, , and Renal l Outcomes in in the CREDENCE Tria ial 30% Reduction in Primary Outcome RENAAL (Losartan) NNT=34 Reduction in Renal Composite Outcomes 16% in RENAAL 20% in IDNT David Z. Cherney et al. J Am Coll Cardiol 2019;74:2511-2524
DAPA-HF HF Prim imary Endpoint Acc ccording to Pre-Specified Subgroups Mc Murray JJV et al. N Engl J Med 2019;381:1995-2008.
Conclusions • Patients with T2DM have high residual risk for the development of cardiovascular complications and diabetic kidney disease progression. • SGLT2 inhibitors have consistently reduced the risk of hospitalization for HF and progression of diabetic kidney disease. • Selection of antihyperglycemic agents in patients with T2DM should take several factors into account, including metabolic requirements, safety, and background presence of CVD, HF, and renal complications. • Ongoing and future trials are required to determine the safety and efficacy of SGLT2 inhibitors in novel settings, including in nondiabetic adults with CVD and/or kidney disease, and in individuals with CVD in the absence of T2DM.
The empagliflozin chronic heart failure program Heart failure Heart failure with preserved with reduced ejection fraction ejection fraction (HFpEF) (HFrEF) Outcomes trial with planned Outcomes trial with planned recruitment: recruitment: LVEF ≤40% 4 LVEF >40% 1 5500 patients 1,2 3350 patients 3,4 Functional capacity study Functional capacity study 300 patients 5,6 300 patients 7,8 Mechanistic study 86 patients 9 LVEF, left ventricular ejection fraction. 1. ClinicalTrials.gov. NCT03057951 2. Butler J et al. ESC-HF 2018; poster P972 3. ClinicalTrials.gov. NCT03057977 4. Zannad F et al. ESC-HF 2018; poster P1755 5. ClinicalTrials.gov. NCT03448406 6. Ponikowski P et al. ESC-HF 2018; poster P302 7. ClinicalTrials.gov. NCT03448419 8. Abraham WT et al. ESC-HF 2018; poster P303 9. ClinicalTrials.gov. NCT03332212
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