interventions in the course of CVD? John E Deanfield, MD London, - PowerPoint PPT Presentation

Session: Diabetes & Cardiovascular Disease: How do they relate? Shifting gears in CVD & T2DM: What is the rationale for new diabetes interventions in the course of CVD? John E Deanfield, MD London, United Kingdom Cardio Diabetes Master Class February 22-23, 2019 - Barcelona, Spain

PACE Cardio Diabetes Master Class Rationale for New Diabetes Treatments for CVD Professor John Deanfield - University College London, UK 22 Feb 2019

Professor John Deanfield: Disclosures ▪ Received CME honoraria and/or consulting fees from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk, Bayer ▪ Member of Study Steering Committees for Novo Nordisk ▪ Research grants from British Heart Foundation, MRC(UK), NIHR, PHE, MSD, Pfizer, Aegerion, Colgate, Roche ▪ No conflicts of interest for this presentation ESC  Munich 2018

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

Ageing: We May Have Hit An Inflexion Point… Source: Office of National Statistics 25 September 2018 Deanfield  UCL

Diabetes Is Associated With Significant Loss of Life Years 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

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 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

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

Benefit of different interventions per 200 patients with diabetes treated for 5 years Using traditional glucose lowering treatments 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 -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

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

Dapagliflozin and CV Outcomes: DECLARE Study Source: S Wiviott et al, N Engl J Med, Nov 2018, DOI: 10.1056/NEJMoa1812389 Deanfield  UCL

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 Patients with event (%) HR: 0.87 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

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

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

DECLARE Trial: Death from Vascular or Other Causes Source: S Wiviott et al, N Engl J Med, Nov 2018, DOI: 10.1056/NEJMoa1812389 Deanfield  UCL

GLP-1RAS have Multifactorial Effects Pancreas Brain  Satiety  Food intake  Glucose-dependent  Body weight insulin secretion  Insulin biosynthesis  Beta-cell apoptosis  Glucose-dependent glucagon secretion Stomach  Gastric emptying Heart Liver  Cardiovascular risk  Cardiac function  Steatosis  Systolic blood pressure  Inflammation  Hepatic insulin sensitivity  Endogenous glucose production  De novo lipogenesis  Lipotoxicity . Campbell JE, Drucker DJ. Cell Metab 2013;17:819 – 37 and Pratley RE, Gilbert M. Rev Diabet Stud 2008;5:73 – 94

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. 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

GLP-1 RA in combination with SGLT2-i better than monotherapy in diabetic patients (on HbA1c) 52 weeks results of the DURATION-8 study Percentage of patients achieving their glycemic and weight targets 40% 35% 30% 25% 20% 15% 10% 5% 0% HbA1c <7.0% HbA1c =<6.5% BW loss =>5% Exenatide + dapagliflozin Exenatide alone Dapagliflozin alone Source: Jabbour et al, Diab Care July 2018, pub ahead of print, doi:10.2337/dc18-0680/-/DC1 Deanfield  UCL

New Diabetes Drugs: Give together? SGLT2 GLP-1RA • Complimentary Actions • Good for HBA1c but no CVOT trials • Specific patient populations? • Guidelines adopting • Price will be an issue Source: Das, S, Everett B et al, J Am Coll Cardiol 2018;72(24):3200-23, 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease Deanfield  UCL

Despite all of the benefits of the GLP- 1RAs… their use is still low compared with OADs GLP-1 RAs have Less than 10% of all people with unprecedented efficacy diabetes are on GLP-1s Deanfield  UCL

How to Organize Best Care for Patients with Diabetes? Diabetologists, Cardiologists, Nephrologists, Primary Care physicians need to be involved in care plan for diabetes patients Deanfield  UCL

Cardiologists must Engage! ➢ Cardiologists need to update It is NOT that themselves on good diabetes care complicated… ➢ Checking the “diabetes” checks have been done is quick ➢ Little additional work Surprise your patient: ➢ Get to know your local diabetologist ask them about and what GPs can offer their diabetes! ➢ Remember to screen for diabetes (HbA1c ≥ 6.5% or FPG ≥ 7 mmol/l) Deanfield  UCL

A Thought… “Why just strive to treat a disease better when you could prevent it?” Deanfield  UCL

Diabetes Epidemic : Risk Factors start Early! 2015 2040 Bjerregaard et al, N Engl J Med 2018;378:1302-12 IDF Diabetes Atlas. 7th edn. 2015 Deanfield  UCL

Obesity at 2 yrs Predicts Status at 35 yrs... Source: Ward et al, N Engl J Med 2017;377:2145-53 Deanfield  UCL

BMI during Adolescence and Outcome Predominantly due to Diabetes and BP Twig G et al, NEJM 2016;374:2430-40

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 Deanfield  UCL

Dysglycaemia and CV risk: Impact of glucose perturbations in patients who have experienced MIs GAMI – long-term follow-up First major event (death, MI, stroke, or severe HF) GAMI-pat Proportion of event-free survival Pat + NGT Pat + DM Pat + IGT Log-rank overall: p=0.0046 Follow-up (years) DM, diabetes mellitus; GAMI, Glucose Tolerance in Patients with Acute Myocardial Infarction; HF, heart failure; IGT, impaired glucose tolerance; MI, myocardial infarction; NGT, normal glucose tolerance; Pat, patients Source: Ritsinger et al, Diab Vasc Dis Res 2015;12:23 – 32 Deanfield  UCL