DKD & cardiovascular risk: What is the potential for targeting GLP-1? Prof. Erik Stroes, MD Amsterdam, The Netherlands June 8, 2020 - Virtual ERA-EDTA
Diabetic Kidney Disease and Cardiovascular Risk: What is the potential for targeting GLP-1? ERA-EDTA online conference Milan, June 2020 Erik S Stroes Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands
Disclosures Speaker fees/ Ad-board fees have been paid to the institution for ES Stroes by: Amgen, Sanofi, Regeneron, Novartis, Astra-Zeneca, Akcea Research grants / participation in clinical trials: Amgen, Sanofi, Astra-Zeneca, Akcea, Esperion Research funding: European Union (FP7, Horizon-2020, ERA-CVD), Dutch Heart Foundation (CVON)
Outline Diabetic Kidney Disease: Unmet residual cardiovascular risk Novel opportunities GLP1 in cardiorenal risk in DKD-patients
Impact of CKD and DM-II on CVD prevalence and mortality Prevalence of CVD categorized Impact of DM-II by type or renal disease on life-years lost Seshasai, N Engl J Med 2011; Provenzano M, Rev Cardiovasc Med 2019
Multifactorial intervention needed in DM-II Ray , Lancet 2009
High residual risk for DM-II patients Using high-dose statin therapy Atorvastatin 80 mg Eze 10 mg / Simva 40 mg Diabetes Diabetes Yes No Yes No 39.8% 26.1% 40.0% 30.2% *Cerebrovascular event, CHF with hospitalisation, CHD death, *Cardiovascular death, non-fatal MI, rehospitalisation for UA, MI, resuscitated cardiac arrest, coronary revascularisation coronary revascularisation (occurring at least 30 days after and documented angina randomisation) or stroke Shepherd et al. Diabetes Care 2006;29:1220 – 6 (TNT); CHD, coronary heart disease; CHF, congestive heart failure; Cannon et al, NEJM 2015;362:2387 – 97 and supplemental data (IMPROVE-IT). CV, cardiovascular; MI, myocardial infarction; UA, unstable angina.
DKD: unmet residual Cardio-Renal Risk Higher CV-risk in DKD: • Traditional risk factors • Independent risk factors Treatment of CV/Renal risk in CKD/DM: • No succes of intensive RR control • No succes of intensive Lipid control • No effect of intensive glucose control Lessey, Vasc Health Risk Man 2019 Papademetriou V, ACCORD trial: Am J Nephrol 2016/2017
Outline Diabetic kidney disease: Unmet residual cardio-renal risk Novel opportunities Anti-inflammatory strategies Targeting calcification GLP1 in cardiorenal risk in DKD-patients
Causes & Consequences of Systemic chronic inflammation (SCI) SCI significant cause of death: >50% of deaths attributable to inflammation-related diseases: ischemic heart disease, cancer, diabetes mellitus , chronic kidney disease , D. Furman, Nat med 2019
Mechanistic pathways for vascular inflammation in DM-II and Kidney Disease Proteinuria/ uremic toxins Pechlivani, Frontiers Cardiov Med 2018
Increased arterial wall inflammation in DM-II Bernelot-Moens , BMC Cardiovascular disorders 2016
Increased arterial wall inflammation in CKD Unresponsive to 3-months lipid-lowering Hoogeveen, JACC CV Imaging 2019; Hoogeveen, Stroes, submitted
Effect of IL1b inhibition in CKD Patients with CKD Patients no CKD Ridker, JACC 2018
Outline Diabetic kidney disease: Unmet residual cardio-renal risk Novel opportunities Anti-inflammatory strategies Targeting calcification GLP1 in cardiorenal risk in DKD-patients
Diabetes & Kidney disease: more atherogenic calcification Association CAC – eGFR 1 MACE according to CAC & GFR 1 CKD associates with more severe CAC/CAC progression w/wo DM 2 , Independent of traditional risk-factors 3 1. Lee, Am J Cardiol 2019; 2. Kramer, JASN 2005, 3. JD Bundy, AJKD 2019
Vit K and Calcification in CKD ? Matrix Gla protein Cozzolino, Adv Chron K Dis 2019
Vascular Calcification in CKD: Role of Vitamin K- Dependent Matrix Gla Protein Vit K suppletion on Vascular Calcification Vit K suppletion on Vascular stiffness Vit K suppletion on MGP DM-CKD: - higher levels of inactive MGP - Inact MGP predictive for all-cause mortality 1. Roumeliotis, Front Med 2020; 2. Roumeliotis, J Diab Complic 2017; 3. JS Lees, Heart 2019
Outline Diabetic kidney disease: Unmet residual cardio-renal risk Novel opportunities Anti-inflammatory strategies Targeting calcification GLP1 in cardiovascular risk in DKD-patients
Recent CVOTs with antidiabetic agents Primary composite endpoint: MACE SGLT2i GLP-1RA Insulin DPP-4i EXAMINE EMPA-REG Outcome ELIXA* ORIGIN Alo vs. Pbo Empa vs. Pbo Lixi vs. Pbo Glargine U100 vs. SOC DEVOTE SAVOR TIMI-53 CANVAS Program FREEDOM-CVO ? Degludec vs. Saxa vs. Pbo Cana vs. Pbo ITCA 650 vs. Pbo Glargine U100 TECOS* DECLARE-TIMI 58 LEADER Sita vs. Pbo Dapa vs. Pbo Lira vs. Pbo CARMELINA SUSTAIN-6 Lina vs. Pbo Sema vs. Pbo EXSCEL Exe OW vs. Pbo HARMONY Alb vs. Pbo REWIND Dul vs. Pbo 0,1 0,4 0,7 1,0 1,3 0,1 0,4 0,7 1,0 1,3 0,1 0,4 0,7 1,0 1,3 1,6 0,1 0,4 0,7 1,0 1,3 HR [95% CI] HR [95% CI] HR [95% CI] HR [95% CI] *MACE+ Pffefer et al. N Engl J Med 2015;373:2247 – 57; Intarcia press *MACE+ release 06 May 2016; Marso et al. N Engl J Med 2016;375:311 – 22; White et al. N Engl J Med 2013; 369:1327 – 35; Zinman et al. N Engl J Med 2015; 373:2117- Marso et al. N Engl J Med 2016;375:1834 – 44; Holman et al . N Engl Scirica et al. N Engl J Med 2013;369:1317 – 26; 28; Neal et al. N Engl J Med 2017;377:644 – J Med 2017;377:1228 – 39; Hernandez et al . Lancet. 2018 Oct Gerstein et al. N Engl J Med 2012;367: Green et al. N Engl J Med 2015;373:232 – 42; 319 – 28; Marso et al. N Engl J Med 2017;377:723 – 57; Wiviott et al. N Engl J Med. 2019 Jan 27;392(10157):1519-1529. ; Gerstein et al . Lancet . 2019 Jun 10. McGuire et al. JAMA . 2019 Jan 1;321(1):69-79. 24;380(4):347-357. http://dx.doi.org/10.1016/S0140-6736(19)31149-3 32
Potential modes of action for GLP-1 receptor activation to impact CVD Drucker. Cell Metab 2016;24:15 – 30
Mechanisms for CV risk reduction ‘multifactorial’ Glycaemia Body weight RR Blood pressure Blood lipids Other mechanisms: Anti-inflammatory? Dalsgaard et al. Diabetes Obes Metab 2018;20:508 – 519;
Direct anti-atherogenic effects of GLP1a Pro-atherogenic M Φ 1 M Φ Atherosclerotic M Φ 2 Macrophage lesion Pro-resolving 25 Semaglutide attenuates plaque *** *** *** lesions in LDLr mice 20 Plaque area (%) 15 10 5 0 Semaglutide Vehicle, Vehicle, Bruen et al. Cardiovasc Diabetol 2017;16:143 1 nmol/kg 3 nmol/kg 15 nmol/kg chow WD Rakipovski et al. JACC Basic Transl Sci 2018
Direct Anti-inflammatory effect of GLP1-agonist in diabetic cardiomyopathy in rats TNF mRNA expression in DM-heart in rats TGFb expression in DM-heart in rats Hussein, Biomedicine 2020
Think CVD in Diabetes!@ Melanie J. Davies et al. Dia Care 2018;41:2669-2701
Summary DKD patients hallmarked by unmet residual cardiovascular risk Beyond traditional CV risk factors Not reversed by traditional CV-therapy Specific interventions are needed to address residual CV risk in DKD patients Anti-inflammatory? Inhibiting calcification? GLP1 agonist have shown to partially address this gap Multifactorial effect (glycemia, weight, blood pressure, lipids) Other ‘direct’ mechanism(s) likely to contribute
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