Shifting gears in CVD & T2DM: What is the rationale for new - 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 November 16 - 17, 2018 - Dubai, UAE

Shifting Gears in CVD and T2DM: What Is The Rationale For New Diabetes Interventions in the Course of CVD? Professor John Deanfield, UCL Dubai, November 2018 PACE Dubai 2018

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 PACE Dubai 2018

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

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 PACE Dubai 2018

Treatment Goals in T2DM in 2018 and beyond… • Management should be targeted at reducing/delaying CV complications in patients with T2DM with and without clinical CVD • Most cardiologists have focused efforts on ‘traditional’ CVRFs and not on glucose lowering Source: Goldner MG, JAMA 1971,218, 1400-10 PACE Dubai 2018

CARDS: Cumulative Hazard for MI and CV Death 15 Relative Risk -37% (95% CI: -52, -17) P=0.001 Cumulative Hazard (%) Placebo 10 Atorvastatin 5 0 0 1 2 3 4 4.75 Years Source: Colhoun Lancet 2004;364:685 – 696 PACE Dubai 2018

Benefit of Different Interventions per 200 Diabetes Patients Treated for 5 years Using traditional Glucose lowering treatments Per 0.9% 5.0 Per 4mm Hg Per 1mmol/L lower HbA1c lower SBP lower LDL-C 0.0 CV Events -2.9 -5.0 -8.2 -10.0 -12.5 -15.0 -20.0 Source: Ray, Lancet 2009 Meta-analysis of intensive glucose-lowering trials PACE Dubai 2018

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

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 PACE Dubai 2018

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

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

Albiglutide and CV Outcomes : HARMONY Trial Composite of All Cause of Death Cardiovascular Death Myocardial Infarction Stroke Source: A Hernandez for the Harmony Outcomes committees and investigators* et al Lancet 2018; 392: 1519 – 29

Renal Benefit from GLP-1RA and SGLT-2i Source: Newman JD, et al, J Am Coll Cardiol 2018; 72(15):1856-69

Evidence Based CV Risk Reduction • Statins • BP Lowering • Metformin GLP1-RA SGLT2-i PACE Dubai 2018

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

SGLT2i trials Composite of Major adverse CV Events Source: Thomas Zelniker et al, Lancet 2018, http://dx.doi.org/10.1016/S0140-6736(18)32590-X

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

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

GLP-1RAs Improve CV and Renal Outcomes Across BP and BMI Source: Leitner an Verma :AHA 2018 Scientific Sessions

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.

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 PACE Dubai 2018

Novel ‘Diabetes’ Drugs: Unanswered Questions ? ? ? Which patients benefit Are these drugs equally Mechanisms by most from each drug? effective in patients without which drugs mediate CVD or without DM e.g. patients with HF or CV benefit? (primary prevention)? kidney disease ? Nephropathy Heart failure Obesity Future CVOTs PACE Dubai 2018

A Question for you…? “Why do we want to be brilliant at treating illnesses that we could have prevented ?”

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

Decline in Smoking vs Rise in Obesity: a Trade Off? 0.4 Smoking rate 0.35 0.3 0.25 Proportion of population 0.2 Obesity rate 0.15 0.1 0.05 0 1970 1974 1978 1982 1986 1990 1994 1998 2002 Year Gruber J and Frakes M. J Health Econ. www.sciencedirect.com.

BMI During Adolescence and CV Mortality 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 PACE Dubai 2018

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 31% 34% Pat + DM Pat + IGT Log-rank overall: p=0.0046 35% 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 PACE Dubai 2018

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 PACE Dubai 2018

Healthy Lifestyle and CVD in T2DM Source: Lui, G et al, JACC 2018;71(25):2867-76 PACE Dubai 2018

SELECT: Trial Design ,Population and Endpoint Semaglutide s.c. 2.4 mg once-weekly N=17,500 patients Male or female Placebo s.c. once-weekly ≥45 years of age BMI ≥ 27 Event driven Randomisation (1:1) 1225 first MACEs Primary endpoint: Time from randomisation to first occurrence of a Prior Prior composite endpoint consisting of either: PAD • CV death MI stroke • Non-fatal myocardial infarction • Non-fatal stroke

New Oral Formulation of SNAC and Semaglutide Semaglutide SNAC Microvilli Intracellular space Columnar epithelial cell Stomach SNAC, Sodium 8-((2-hydroxybenzoyl)amino)octanoate monosodium