Diabetes and CKD: is it all about managing glucose Melanie J Davies CBE FMedSci Professor of Diabetes Medicine
Agenda • Metabolic-cardio-renal cross-talk and role of GLP-1RA • Glucose lowering in T2D and CKD • Summary
Patients with T2D are at increased risk of complications such as CV disease, HF and CKD CKD affects ∽ 50% of patients with • • ~55% with T2D have NAFLD 1 T2D 7 • Over half of patients with T2D • Diabetes is the most common are reported to be obese 2 T2D reason for progression to ESKD, accounting for 30-50% of ESKD 8 • Approximately one in three patients with T2D has CV disease 3 • 2- to 5-fold increased risk of HF in patients with T2D* 4 CV disease/ • 60–80% greater probability of CKD CV death and all-cause mortality HF • 17–21% of patients with CKD in those with T2D and also have HF 9 established HF 5,6 • Presence of CKD in patients with HF increases risk of mortality by ~25–30% 10 *Patients with T2D aged <55 years CKD, chronic kidney disease; CV, cardiovascular; DKD, diabetic kidney disease; ESKD, end-stage kidney disease; HF, heart failure; HHF, hospitalisation for heart failure; T2D, type 2 diabetes 1. Younossi ZM et al. J Hepatology 2019;71:793; 2. Masmiquel L et al. Cardiovasc Diabetol 2016;15:29; 3. International Diabetes Foundation. Diabetes Atlas 8th Edition. http://www.diabetesatlas.org (accessed Jan 2020); 4. Rosengren A et al. Diabetologia 2018;61:2300; 5. Mozaffarian D et al. Circulation 2016;133:e38; 6. MacDonald MR et al. Eur Heart J 2008;29:1377; 7. Thomas M et al. Nat Rev Nephrol 2016;12:73; 8. Toth-Manikowski S & Atta MG. J Diabetes Res 2015;2015:697010; 9. World Health Organisation. https://www.who.int/bulletin/volumes/96/6/17-206441/en/ (accessed Jan 2020); 10. Ather S et al. J Am Coll Cardiol 2012;59:998.
The cardiovascular, renal and metabolic systems are interrelated The heart is the most metabolically demanding organ, susceptible to changes in volume or metabolism 1 Regulation of energy metabolism is essential for The kidneys play a key role in glucose and volume homeostasis 3,4 healthy function, especially in the heart and kidneys 1,2 1. Lopashuk GD & Ussher JR. Circ Res 2016;119:1173; 2. de Boer IH & Utzschneider KM. Nephrol Dial Transplant 2017;32:588; 3. García-Donaire JA & Ruilope LM. Int J Nephrol 2011;2011:975782; 4. Alsahli M & Gerich JE Diabetes Res Clin Pract 2017;133:1
Dysfunction of the heart, kidneys or metabolism contributes to the dysfunction of the others 1,2 Diseases of the CRM system share many of the same risk factors 3 • Dysfunction in one system leads to progression of interrelated diseases 4 such as T2D , CV disease, • HF, and CKD , which in turn lead to an increased risk of CV death 5 Cardiovascular Energy Renal metabolism CKD, chronic kidney disease; CRM, cardio-renal-metabolic; CV, cardiovascular; HF, heart failure; T2D, type 2 diabetes CRM, cardio-renal-metabolic; CV, cardiovascular; HF, heart failure; T2D, type 2 diabetes 1. García-Donaire JA & Ruilope LM. Int J Nephrol 2011;2011:975782; 2. Thomas G et al. Clin J Am Soc Nephrol 2011;6:2364; 3. Sarafidis PA et al. J Cardiometab Syndr 2006:58; 4. Ronco C et al. Contrib Nephrol 2010;165:54; 5. Leon BM and Maddox TM. World J Diabetes 2015;6:1246
Metabolic dysfunction adds to cardio–renal disease progression and outcomes 1,2 Cardiac failure 2 Vascular dysfunction 1 Atherosclerosis 2 Energy metabolism Glucotoxicity Fluid retention 2 Lipotoxicity 1 Albuminuria 1 ↑ Insulin resistance 1 Renal failure 1 Altered hormonal milieu 1 ↑ Adipokines 1 1. Connell AW & Sowers JR. J Am Soc Hypertens 2014;8:604; 2. Ronco C et al. J Am Coll Cardiol 2008;52:1527
Cardiac dysfunction adds to the renal/metabolic burden 1,2 Cardiac abnormalities affect renal/metabolic disease progression and outcomes 1,2 Hypoperfusion 2 Cardiovascular Volume overload 2 ↑ Arterial resistance 2 Neurohormonal activation 1,2 ∆ Substrate utilisation 3 Autonomic dysfunction 1,2 Hypertension 1,2 ↑ Insulin resistance 1 Albuminuria 1,2 ↑ FFA and Renal failure 1 lipotoxicity 4 FFA, free fatty acids 1. Connell AW & Sowers JR. J Am Soc Hypertens 2014;8:604; 2. Ronco C et al. J Am Coll Cardiol 2008;52:1527; 4. Lopashuk GD & Ussher JR. Circ Res 2016;119:1173
Renal dysfunction adds to cardiac and metabolic burden Renal abnormalities affect cardiac and metabolic disease progression and outcomes 1,2 Ventricular hypertrophy 2 Cardiac failure 2 Vascular dysfunction 1,2 Atherosclerosis 2 Renal 1,2 Hypertension ↑ Insulin resistance 1 Fluid retention ↑ Hypoglycaemia Oxidative stress Arterial calcification Activation of the RAAS & SNS RAAS, renin–angiotensin–aldosterone system; SNS, sympathetic nervous system 1. Connell AW & Sowers JR. J Am Soc Hypertens 2014;8:604; 2. Cabundugama PK et al. Med Clin North Am 2017;101:129
GLP-1 in the treatment of diabetes …that works on many GLP-1, the conductor of the important organs diabetes orchestra… Lowering of blood glucose Increased insulin, lowered glucagon, gastric emptying Lowering of body weight Lowered food intake, increased satiety, reduced hunger Cardiovascular effects Reduced blood pressure, lipids, inflammation Drucker D. Cell Metab 2016;24:15–30
Effects of GLP-1 receptor agonists on the cardio-renal-metabolic systems GLP-1 RA Intermediate Effects Downstream observed effects Insulin CV events secretion Glucagon Blood pressure suppression Inflammation Coagulation Body weight Natriuresis Postprandial lipids LV function Diuresis HbA1c GLP-1 RA, glucagon-like peptide-1 receptor agonist Adapted from Drucker D. Cell Metab 2018;27:740; Rizzo M et al. Biochim Biophys Acta Mol Basis Dis 2018;1864:2814
Agenda • Metabolic-cardio-renal cross-talk and role of GLP-1RA • Glucose lowering in T2D and CKD • Summary
Limited CV benefits have been observed with intensive glycaemic control in patients with T2D Meta-analysis of the ACCORD, ADVANCE, UKPDS and VADT studies Objective: to generate precise estimates All-cause Major CV of the effects of glucose-lowering mortality events therapy on major CV events Patients with T2D (N=27,049) allocated to ‘More intensive’ No effect Limited benefit or ‘Less intensive’ glycaemic HR 1.04 (0.90, 1.20) HR 0.91 (0.84, 0.99) control Turnbull FM et al. Diabetologia 2009;52:2288
Multifactorial control of CV risk factors reduced CV risk in T2D patients Steno-2: Intensive multifactorial control of CV risk factors reduces CV risk in patients with T2D and microalbuminuria Unadjusted HR 0.55 (95% CI 0.39, 0.77); p =<0.001 Conventional (51 events) Intensive (35 events) Composite end-point: time to incident CVD, number of CV events, mortality and CVD rates CV, cardiovascular; CVD, cardiovascular disease; T2D, type 2 diabetes Gaede P et al. Diabetologia 2016;59:2298
Multifactorial management established as standard of care for patients with T2D 1,2 Management approaches focus on reducing the risk of CV death in patients with T2D 1,2 Target Treatment For individuals with T2D and hypertension, a blood pressure • RAAS blocker, and a calcium channel Blood pressure- target of: blocker or diuretic <130/80 mmHg if at higher CV risk * 1 lowering • • Dual therapy is recommended as first- <140/90 mmHg if at lower risk for CV disease †1 • line treatment • <1.8 mmol/l (<70 mg/dl) with LDL-C reduction of LDL cholesterol- ≥50% if at high CV risk • Statins, ezetimibe or a PCSK9 inhibitor lowering • <2.6 mmol/l (<100 mg/dl) if at moderate CV risk • SGLT2 inhibitors ‡ , GLP-1 RA § , DPP-4 Glucose control Targets are individualised – generally HbA1c <7% inhibitors, metformin, sulfonylureas, thiazolidinediones, insulin • Diet Individualised Weight loss and smoking cessation • Physical activity diet and lifestyle • Behavioural therapy *Existing ASCVD or 10- year ASCVD risk ≥15%; † 10-year ASCVD risk <15%; ‡ Empagliflozin, canagliflozin, and dapagliflozin reduce CV events in patients with DM and CVD or are at very high/high CV risk; § Liraglutide, semaglutide and dulaglutide reduce CV events in patients with DM and CVD, or who are at very high/high CV risk ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular; HbA1c, glycated haemoglobin; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9; T2D, Type 2 Diabetes; RAAS, renin-angiotensin-aldosterone system 1. American Diabetes Association. Diabetes Care 2020;43:S1; 2. Cosentino F et al. Eur Heart J 2020;7:255
Effects of drug classes on CV, HF and kidney outcomes SGLT2i GLP1-RA ACEi ARB Statins MACE † * CV death HHF Hard renal endpoints Albuminuria All-cause mortality Not intended for direct comparison; comparison of trials should be interpreted with caution due to differences in study design, populations and methodology *Empagliflozin only; † Liraglutide only; ‡ Most commonly doubling serum creatinine, ESKD, renal death ACEi, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor-neprilysin inhibitor; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; GLP1-RA, glucagon-like peptide-1 receptor agonist; HHF, hospitalisation for heart failure; MACE, major adverse cardiovascular events; SGLT2i, sodium-glucose co-transporter-2 inhibitor
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