Prof. John E Deanfield, MD London, United Kingdom Asian Cardio - PowerPoint PPT Presentation

New Frontiers in CVD, Diabetes & CKD Targeting risk in patients with CVD, Diabetes or CKD: new guidelines and risk management approaches Prof. John E Deanfield, MD London, United Kingdom Asian Cardio Diabetes Forum March 30-31, 2019 - Hanoi, Vietnam

Professor John Deanfield: Disclosures ▪ Received CME honoraria and/or consulting fees from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk, Bayer ▪ Research grants from British Heart Foundation, MRC(UK), NIHR, PHE, MSD, Pfizer, Aegerion, Colgate, Roche ▪ No conflicts of interest for this presentation ▪ Member of SOUL and SELECT Study Steering Committees for Novo Nordisk Deanfield  UCL

Healthy Ageing? CV Disease is the Major Cause of Morbidity and Mortality Deanfield  UCL

CVD Challenge in Diabetes is Clear Vascular deaths Non-vascular deaths 7 Men Women 6 7 5 Years of life lost 6 4 5 3 4 2 3 1 2 0 1 0 40 50 60 70 80 90 0 40 50 60 70 80 90 0 Age (years) Age (years) On average, a 50-year old with diabetes but no history of vascular disease is ~6 years younger at time of death than a counterpart without diabetes Source: Seshasai et al, N Engl J Med 2011; 364:829-41 Deanfield  UCL

Diabetes UK: The Impact of Diabetes Today Source: Diabetes UK

DM and 1-yr Composite Outcome and All-cause Mortality for ASIAN-HF Men and Women 4 X Hospitalization for Heart Failure in Diabetes Source: Chandramouli C et al, EJHF, (2019) 21, 297 – 307 Deanfield  UCL

Major Diabetes Complications in USA Hyperglycaemic Deaths CVD Admissions PACE Dubai 2018 Deanfield  UCL

Treatment Goals in T2DM Management should be targeted at reducing / delaying CV complications in patients with T2DM with and without clinical CVD Not just icing on the cake!!! Deanfield  UCL

Insulin Resistance: An Inflammatory Atherothrombotic Syndrome Hyperinsulinaemia Hyperglycaemia Triglyceride INSULIN RESISTANCE Cholesterol Insulin Resistance PAI-1 tPA Hypertension Factor VII Factor XII CRP Fibrinogen Smoking Monocytes Cytokines Adhesion Molecules Deanfield  UCL

Risk Factors for CVD in patients with T2DM 271,174 pts with T2DM matched to 1,355,870 controls Median F/U = 5.7 years with 175,345 deaths Death From Any Cause Acute Myocardial Infarction Stroke Heart Failure Source: Rawshani et al, N Engl J Med 2018;379:633-44 Deanfield  UCL

Benefit of different interventions per 200 patients with diabetes treated for 5 years 5 Per 4mm Hg Per 1mmol/L Per 0.9% lower SBP lower LDL-C lower HbA 1c 0 CV Events -2.9 -5 -8.2 -10 -12.5 -15 Using traditional glucose lowering treatments -20 Source: Ray, Lancet 2009 Meta-analysis of intensive glucose-lowering trials. Deanfield  UCL

Diabetes Medications and Increased CV Risk Source: Nissen SE, Wolski K. N Engl J Med 2007; 356: 2457-2471 Deanfield  UCL

Diabetes Medications and Possible Increased CV Risk ▪ Sulphonyl Ureas FDA / EMA requirements: ▪ Thiazolidinediones ▪ New diabetes drugs should demonstrate ▪ DPP-4 Inhibitors CV safety with meta-analysis and CV ▪ Insulin outcome trial ESC  Munich 2018

GLP-1RA CV Outcome Trials SUSTAIN 6 LEADER Time to first occurrence of CV death, non-fatal MI or non-fatal stroke 2 0 HR: 0.74 (95% CI: 0.58 ; 0.95) p <0.001 for non-inferiority HR: 0.87 Patients with event (%) p =0.02 for superiority Patients with event (%) (95% CI: 0.78 ; 0.97) Placebo 1 5 p <0.001 for non-inferiority p =0.01 for superiority Placebo 1 0 Liraglutide Semaglutide 5 0 0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 Time from randomisation (months) Time from randomisation (months) Marso SP et al. N Engl J Med 2016;375:311 – 322 Marso SP et al. N Engl J Med 2016;375:1834 – 1844 Deanfield  UCL

Empagliflozin, CV Outcomes and Mortality in T2DM Primary Outcome Death from Cardiovascular Causes Death from Any Cause Hospitalization for Heart Failure Source: Zinman N Engl J Med 2015;373:2117-28 Deanfield  UCL

CVD-REAL 2: Lower CV Risk Associated With SGLT-2 i 6 Countries Asia Pacific, Middle East, North America -27% established CVD Source: Kosiborod, M. et al. J Am Coll Cardiol. 2018;71(23):2628 – 39. Deanfield  UCL

Diabetes Treatment for CVD Reduction SGLT-2 Inhibitors GLP-1R Agonists Deanfield  UCL Source: Newman JD, et al, J Am Coll Cardiol 2018; 72(15):1856-69

Four weeks of liraglutide inhibits progression of atherosclerotic lesions in ApoE -/- mice Lesion development Intima‒media ratio (IMR) Lipid deposition * 15 N=13‒16 N=6‒10 0.4 Lesion area (%) 0.3 M 10 M IMR 0.2 I I 5 M 0.1 Vehicle Lira Lira + Ex-9 0.0 0 Vehicle Lira Lira + Ex-9 Vehicle Lira Lira + Ex-9 IMR analysis performed Haemotoxylin and eosin staining Oil red O staining performed in the aortic arch in the aortic arch in the aorta Gaspari T et al. Diab Vasc Dis Res 2013;10:353‒60.

Meta-analysis of SGLT2i trials on hospitalisation for Heart Failure and CV death by established Atherosclerotic CV disease Source : Zelniker, T et al., Lancet 2019; 393: 31 – 39 Deanfield  UCL

Meta-analysis of SGLT2i trials on the composite of Renal Worsening, ESRD, or Renal Death by established Atherosclerotic CV disease Source : Zelniker, T et al., Lancet 2019; 393: 31 – 39 Deanfield  UCL

Meta-analysis of SGLT2i trials on the composite of Myocardial Infarction, Stroke, and CV death (major adverse CV events) by Heart Failure Source : Zelniker, T et al., Lancet 2019; 393: 31 – 39 Deanfield  UCL

Diabetes is very common in Heart Failure Medical History HF-REF (%) HF-PEF (%) p value IHD 48.4 37.9 <0.001 Atrial fibrillation 49.1 40 0.857 MI 30.7 18.1 <0.001 <0.001 Valve disease 23.9 31.4 <0.001 Hypertension 52.1 59.9 Diabetes 33.3 33.5 0.577 <0.001 Asthma 8.4 9.4 <0.001 COPD 16.7 18.9

NHE-dependent Pathways That May Underlie the Interplay of Pathogenesis of HF and DM Source : Packer, M, Circulation. 2017;136:1548 – 1559 Deanfield  UCL

Novel ‘Diabetes’ Drugs: Unanswered Questions ? ? ? Which patients benefit Mechanisms by Are these drugs equally most from each drug? which drugs mediate effective in patients without CV benefit? CVD or without DM e.g. patients with HF or ‘Bedside to Bench!’ (primary prevention)? kidney disease ? Nephropathy Heart failure Obesity Future CVOTs Deanfield  UCL

The Ticking Clock:  CV Risk Before  Glucose (Nurses’ Health Study) 20 yr F/U of 117,629 women: n=1,508 diabetes at B/L; n=5,894 developed diabetes; n=110,227 free from diabetes 6.0 Relative risk of MI or stroke 5.02 5.0 4.0 3.71 2.82 3.0 2.0 1.0 1.0 0.0 Nondiabetic Risk of event Risk of event Diabetic throughout prior to after DM at B/L the study DM diagnosis diagnosis Source: Hu et al, Diabetes Care 2002; 25: 1129-1134 PACE Dubai 2018

SGLT2i In Different Patient Populations Source : Verma,S, et al, Lancet, Vol 393 January 5, 2019, 3-5 Deanfield  UCL

CVOT Impact on Clinical Guidelines ADA 2018 recommendation In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, antihyperglycemic therapy should begin with lifestyle management and metformin and subsequently incorporate an agent proven to reduce major adverse cardiovascular events and cardiovascular mortality (currently, empagliflozin and liraglutide), after considering drug-specific and patient factors (Table 8.1). Source: American Diabetes Association. Diabetes Care 2018;41 (Suppl 1):S73 – S85 Deanfield  UCL

Exciting New Era for CVD Management in DM ▪ Opportunity to improve outcomes in Diabetologists Cardiologists millions of patients with diabetes ▪ Likely to be benefits beyond current evidence from trials ▪ Transform clinical care including the Nephrology Primary Care preclinical phase of cardiometabolic risk Deanfield UCL

Evidence Based CV Risk Reduction • Statins • BP Lowering • Metformin GLP1-RA SGLT2-i Deanfield  UCL

How to Organize Best Care for Patients with Diabetes? Diabetologists, Cardiologists, Nephrologists, Primary Care physicians need to work together in care plan Deanfield  UCL

Diabetes Treatment for CVD Reduction SGLT-2 Inhibitors GLP-1R Agonists Deanfield  UCL Source: Newman JD, et al, J Am Coll Cardiol 2018; 72(15):1856-69

Outcome Benefits in EMPA -REG OUTCOME, LEADER, and SUSTAIN 6 Trials 40 40 30 30 20 20 10 10 0 0 % % -10 -10 -20 -20 -30 -30 -40 -40 EMPA-REG LEADER SUSTAIN 6 EMPA-REG LEADER SUSTAIN 6 MI Stroke CV Death HF Hospitalisation Source: Sattar J Am Coll Cardiol 2017;69:2646 – 2656 Deanfield  UCL