What is the potential for targeting GLP-1? Prof. Erik Stroes, MD - - PowerPoint PPT Presentation

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What is the potential for targeting GLP-1? Prof. Erik Stroes, MD - - PowerPoint PPT Presentation

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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

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DKD & cardiovascular risk: What is the potential for targeting GLP-1?

  • Prof. Erik Stroes, MD

Amsterdam, The Netherlands

June 8, 2020 - Virtual ERA-EDTA

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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

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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)

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Outline Diabetic Kidney Disease: Unmet residual cardiovascular risk Novel opportunities GLP1 in cardiorenal risk in DKD-patients

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Impact of CKD and DM-II

  • n CVD prevalence and mortality

Seshasai, N Engl J Med 2011; Provenzano M, Rev Cardiovasc Med 2019

Prevalence of CVD categorized by type or renal disease Impact of DM-II

  • n life-years lost
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Multifactorial intervention needed in DM-II

Ray, Lancet 2009

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CHD, coronary heart disease; CHF, congestive heart failure; CV, cardiovascular; MI, myocardial infarction; UA, unstable angina. Shepherd et al. Diabetes Care 2006;29:1220–6 (TNT); Cannon et al, NEJM 2015;362:2387–97 and supplemental data (IMPROVE-IT).

High residual risk for DM-II patients

Using high-dose statin therapy Atorvastatin 80 mg Diabetes Yes No 39.8% 26.1% Eze 10 mg / Simva 40 mg Diabetes Yes No 40.0% 30.2%

*Cardiovascular death, non-fatal MI, rehospitalisation for UA, coronary revascularisation (occurring at least 30 days after randomisation) or stroke *Cerebrovascular event, CHF with hospitalisation, CHD death, MI, resuscitated cardiac arrest, coronary revascularisation and documented angina

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DKD: unmet residual Cardio-Renal Risk

Lessey, Vasc Health Risk Man 2019 Papademetriou V, ACCORD trial: Am J Nephrol 2016/2017

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
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Outline Diabetic kidney disease: Unmet residual cardio-renal risk Novel opportunities Anti-inflammatory strategies Targeting calcification GLP1 in cardiorenal risk in DKD-patients

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Causes & Consequences of Systemic chronic inflammation (SCI)

  • D. Furman, Nat med 2019

SCI significant cause of death: >50% of deaths attributable to inflammation-related diseases: ischemic heart disease, cancer, diabetes mellitus, chronic kidney disease,

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Mechanistic pathways for vascular inflammation in DM-II and Kidney Disease

Pechlivani, Frontiers Cardiov Med 2018

Proteinuria/ uremic toxins

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Increased arterial wall inflammation in DM-II

Bernelot-Moens, BMC Cardiovascular disorders 2016

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Increased arterial wall inflammation in CKD

Unresponsive to 3-months lipid-lowering

Hoogeveen, JACC CV Imaging 2019; Hoogeveen, Stroes, submitted

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Patients with CKD Patients no CKD

Effect of IL1b inhibition in CKD

Ridker, JACC 2018

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Outline Diabetic kidney disease: Unmet residual cardio-renal risk Novel opportunities Anti-inflammatory strategies Targeting calcification GLP1 in cardiorenal risk in DKD-patients

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Diabetes & Kidney disease:

more atherogenic calcification

Association CAC – eGFR1 MACE according to CAC & GFR1

CKD associates with more severe CAC/CAC progression w/wo DM2, Independent of traditional risk-factors3

  • 1. Lee, Am J Cardiol 2019; 2. Kramer, JASN 2005, 3. JD Bundy, AJKD 2019
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Vit K and Calcification in CKD ?

Matrix Gla protein

Cozzolino, Adv Chron K Dis 2019

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Vascular Calcification in CKD: Role of Vitamin K- Dependent Matrix Gla Protein

  • 1. Roumeliotis, Front Med 2020; 2. Roumeliotis, J Diab Complic 2017; 3. JS Lees, Heart 2019

DM-CKD:

  • higher levels of inactive MGP
  • Inact MGP predictive for all-cause mortality

Vit K suppletion on Vascular Calcification Vit K suppletion on Vascular stiffness Vit K suppletion on MGP

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Outline Diabetic kidney disease: Unmet residual cardio-renal risk Novel opportunities Anti-inflammatory strategies Targeting calcification GLP1 in cardiovascular risk in DKD-patients

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EXAMINE Alo vs. Pbo EMPA-REG Outcome Empa vs. Pbo ELIXA* Lixi vs. Pbo ORIGIN Glargine U100 vs. SOC SAVOR TIMI-53 Saxa vs. Pbo CANVAS Program Cana vs. Pbo FREEDOM-CVO ITCA 650 vs. Pbo DEVOTE Degludec vs. Glargine U100 TECOS* Sita vs. Pbo DECLARE-TIMI 58 Dapa vs. Pbo LEADER Lira vs. Pbo CARMELINA Lina vs. Pbo SUSTAIN-6 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 HR [95% CI]

Insulin

?

0,1 0,4 0,7 1,0 1,3 1,6 HR [95% CI]

GLP-1RA

0,1 0,4 0,7 1,0 1,3 HR [95% CI]

DPP-4i

0,1 0,4 0,7 1,0 1,3 HR [95% CI]

SGLT2i

Recent CVOTs with antidiabetic agents

Primary composite endpoint: MACE

*MACE+ White et al. N Engl J Med 2013; 369:1327–35; Scirica et al. N Engl J Med 2013;369:1317–26; Green et al. N Engl J Med 2015;373:232–42; McGuire et al. JAMA. 2019 Jan 1;321(1):69-79. Zinman et al. N Engl J Med 2015; 373:2117- 28; Neal et al. N Engl J Med 2017;377:644– 57; Wiviott et al. N Engl J Med. 2019 Jan 24;380(4):347-357. *MACE+ Pffefer et al. N Engl J Med 2015;373:2247–57; Intarcia press release 06 May 2016; Marso et al. N Engl J Med 2016;375:311–22; Marso et al. N Engl J Med 2016;375:1834–44; Holman et al. N Engl J Med 2017;377:1228–39; Hernandez et al. Lancet. 2018 Oct 27;392(10157):1519-1529.; Gerstein et al. Lancet. 2019 Jun 10. http://dx.doi.org/10.1016/S0140-6736(19)31149-3 Gerstein et al. N Engl J Med 2012;367: 319–28; Marso et al. N Engl J Med 2017;377:723– 32

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  • Drucker. Cell Metab 2016;24:15–30

Potential modes of action for GLP-1 receptor activation to impact CVD

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Mechanisms for CV risk reduction ‘multifactorial’

Dalsgaard et al. Diabetes Obes Metab 2018;20:508–519;

Other mechanisms: Anti-inflammatory?

Glycaemia Body weight Blood pressure Blood lipids

RR

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Direct anti-atherogenic effects of GLP1a

MΦ MΦ1 MΦ2

Macrophage Pro-atherogenic Pro-resolving Atherosclerotic lesion Bruen et al. Cardiovasc Diabetol 2017;16:143 Rakipovski et al. JACC Basic Transl Sci 2018

25 20 15 10 5

*** *** ***

Plaque area (%)

Vehicle, chow Vehicle, WD Semaglutide

1 nmol/kg 3 nmol/kg 15 nmol/kg

Semaglutide attenuates plaque lesions in LDLr mice

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Direct Anti-inflammatory effect of GLP1-agonist in diabetic cardiomyopathy in rats

Hussein, Biomedicine 2020

TNF mRNA expression in DM-heart in rats TGFb expression in DM-heart in rats

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Think CVD in Diabetes!@

Melanie J. Davies et al. Dia Care 2018;41:2669-2701

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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