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

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interventions in the course of cvd john e deanfield md
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interventions in the course of CVD? John E Deanfield, MD London, - - PowerPoint PPT Presentation

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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

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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

Session: Diabetes & Cardiovascular Disease: How do they relate?

Cardio Diabetes Master Class

February 22-23, 2019 - Barcelona, Spain

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PACE Cardio Diabetes Master Class Rationale for New Diabetes Treatments for CVD

Professor John Deanfield - University College London, UK 22 Feb 2019

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ESC  Munich 2018

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

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Healthy Ageing?

CV Disease is the Major Cause of Morbidity and Mortality

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Deanfield  UCL

Ageing: We May Have Hit An Inflexion Point…

Source: Office of National Statistics 25 September 2018

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Diabetes Is Associated With Significant Loss of Life Years

Source: Seshasai et al, N Engl J Med 2011; 364:829-41

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 Men Women

7 6 5 4 3 2 1 40 50 60 70 80 90 Age (years) Years of life lost 7 6 5 4 3 2 1 40 50 60 70 80 90 Age (years) Vascular deaths Non-vascular deaths

Deanfield  UCL

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Major Diabetes Complications in USA

PACE Dubai 2018

CVD Admissions Hyperglycaemic Deaths

Deanfield  UCL

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Deanfield  UCL

Treatment Goals in T2DM Management should be targeted at reducing / delaying CV complications in patients with T2DM with and without clinical CVD

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Risk Factors for CVD in patients with T2DM

Source: Rawshani et al, N Engl J Med 2018;379:633-44 Stroke Heart Failure Death From Any Cause Acute Myocardial Infarction

271,174 pts with T2DM matched to 1,355,870 controls Median F/U = 5.7 years with 175,345 deaths

Deanfield  UCL

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Insulin Resistance: An Inflammatory Atherothrombotic Syndrome

INSULIN RESISTANCE

Hyperglycaemia Hyperinsulinaemia Hypertension

Smoking

Fibrinogen Factor VII Factor XII PAI-1 tPA Triglyceride Cholesterol

CRP Monocytes Cytokines Adhesion Molecules

Insulin Resistance

Deanfield  UCL

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Benefit of different interventions per 200 patients with diabetes treated for 5 years

Using traditional glucose lowering treatments

Source: Ray, Lancet 2009 Meta-analysis of intensive glucose-lowering trials.

Per 0.9% lower HbA1c Per 4mm Hg lower SBP Per 1mmol/L lower LDL-C CV Events 5

  • 5
  • 12.5
  • 15
  • 20
  • 10
  • 8.2
  • 2.9

Deanfield  UCL

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Diabetes Medications and Increased CV Risk

Source: Nissen SE, Wolski K. N Engl J Med 2007; 356: 2457-2471 Deanfield  UCL

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Empagliflozin, CV Outcomes and Mortality in T2DM

Source: Zinman N Engl J Med 2015;373:2117-28

Primary Outcome Death from Cardiovascular Causes Death from Any Cause Hospitalization for Heart Failure

Deanfield  UCL

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Dapagliflozin and CV Outcomes: DECLARE Study

Source: S Wiviott et al, N Engl J Med, Nov 2018, DOI: 10.1056/NEJMoa1812389 Deanfield  UCL

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Marso SP et al. N Engl J Med 2016;375:311–322 Marso SP et al. N Engl J Med 2016;375:1834–1844

LEADER

Time to first occurrence of CV death, non-fatal MI or non-fatal stroke

6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 5 1 0 1 5 2 0

Patients with event (%)

Placebo Liraglutide HR: 0.87 (95% CI: 0.78 ; 0.97) p<0.001 for non-inferiority p=0.01 for superiority

Time from randomisation (months)

SUSTAIN 6

Semaglutide Placebo

Patients with event (%)

HR: 0.74 (95% CI: 0.58 ; 0.95) p<0.001 for non-inferiority p=0.02 for superiority

Time from randomisation (months)

GLP-1RA CV Outcome Trials

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Source: Newman JD, et al, J Am Coll Cardiol 2018; 72(15):1856-69

Diabetes Treatment for CVD Reduction

SGLT-2 Inhibitors GLP-1R Agonists

Deanfield  UCL

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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 Valve disease 23.9 31.4 <0.001 Hypertension 52.1 59.9 <0.001

Diabetes 33.3 33.5 0.577

Asthma 8.4 9.4 <0.001 COPD 16.7 18.9 <0.001

Diabetes is very common in Heart Failure

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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

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. Campbell JE, Drucker DJ. Cell Metab 2013;17:819–37 and Pratley RE, Gilbert M. Rev Diabet Stud 2008;5:73–94

 Cardiovascular risk  Cardiac function  Systolic blood pressure  Inflammation Liver Brain Pancreas Stomach  Steatosis  Hepatic insulin sensitivity  Endogenous glucose production  De novo lipogenesis  Lipotoxicity  Glucose-dependent insulin secretion  Insulin biosynthesis  Beta-cell apoptosis  Glucose-dependent glucagon secretion  Satiety  Food intake  Body weight  Gastric emptying Heart

GLP-1RAS have Multifactorial Effects

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Four weeks of liraglutide inhibits progression of atherosclerotic lesions in ApoE-/- mice

Gaspari T et al. Diab Vasc Dis Res 2013;10:353‒60.

IMR

0.4 0.3 0.2 0.1 0.0

Vehicle Lira Lira + Ex-9

* IMR analysis performed in the aortic arch

Intima‒media ratio (IMR)

N=6‒10

Lesion area (%)

15 10 5

Vehicle Lira Lira + Ex-9

Oil red O staining performed in the aorta

Lipid deposition

N=13‒16

Vehicle Lira Lira + Ex-9

M M I M I

Lesion development

Haemotoxylin and eosin staining in the aortic arch

Deanfield  UCL

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Novel ‘Diabetes’ Drugs: Unanswered Questions

Which patients benefit most from each drug? e.g. patients with HF or kidney disease Mechanisms by which drugs mediate CV benefit? ‘Bedside to Bench!’

? ?

Are these drugs equally effective in patients without CVD or without DM (primary prevention)?

?

Future CVOTs

Heart failure Nephropathy Obesity

?

Deanfield  UCL

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GLP-1 RA in combination with SGLT2-i better than monotherapy in diabetic patients (on HbA1c)

52 weeks results of the DURATION-8 study

0% 5% 10% 15% 20% 25% 30% 35% 40% HbA1c <7.0% HbA1c =<6.5% BW loss =>5% Percentage of patients achieving their glycemic and weight targets 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

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New Diabetes Drugs: Give together?

Deanfield  UCL

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

SGLT2

GLP-1RA

  • Complimentary Actions
  • Good for HBA1c but no CVOT trials
  • Specific patient populations?
  • Guidelines adopting
  • Price will be an issue
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Despite all of the benefits of the GLP-1RAs… their use is still low compared with OADs

Less than 10% of all people with diabetes are on GLP-1s GLP-1 RAs have unprecedented efficacy

Deanfield  UCL

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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

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➢ Cardiologists need to update themselves on good diabetes care ➢ Checking the “diabetes” checks have been done is quick ➢ Little additional work ➢ Get to know your local diabetologist and what GPs can offer ➢ Remember to screen for diabetes

(HbA1c ≥ 6.5% or FPG ≥ 7 mmol/l)

Cardiologists must Engage!

It is NOT that complicated… Surprise your patient: ask them about their diabetes!

Deanfield  UCL

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A Thought…

“Why just strive to treat a disease better when you could prevent it?”

Deanfield  UCL

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IDF Diabetes Atlas. 7th edn. 2015

2015 2040

Bjerregaard et al, N Engl J Med 2018;378:1302-12

Diabetes Epidemic : Risk Factors start Early!

Deanfield  UCL

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Obesity at 2 yrs Predicts Status at 35 yrs...

Source: Ward et al, N Engl J Med 2017;377:2145-53 Deanfield  UCL

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BMI during Adolescence and Outcome

Twig G et al, NEJM 2016;374:2430-40

Predominantly due to Diabetes and BP

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The Ticking Clock:  CV Risk Before  Glucose (Nurses’ Health Study)

Source: Hu et al, Diabetes Care 2002; 25: 1129-1134

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

0.0 Relative risk of MI or stroke Nondiabetic throughout the study Risk of event prior to DM diagnosis Risk of event after DM diagnosis Diabetic at B/L 6.0 5.0 4.0 3.0 2.0 1.0 5.02 3.71 2.82 1.0

Deanfield  UCL

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Dysglycaemia and CV risk: Impact of glucose perturbations in patients who have experienced MIs

Source: Ritsinger et al, Diab Vasc Dis Res 2015;12:23–32

GAMI – long-term follow-up First major event (death, MI, stroke, or severe HF)

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

GAMI-pat

Pat + NGT Pat + DM Pat + IGT Log-rank overall: p=0.0046

Proportion of event-free survival Follow-up (years)

Deanfield  UCL

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CV RF lowering likely to be key: Observational Data

Rawshani et al. N Engl J Med 2018;379:633-644.

Excess mortality to range of risk factor control Excess acute myocardial infarction in relation to range of risk factor control

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Healthy Lifestyle and CVD in T2DM

Source: Lui, G et al, JACC 2018;71(25):2867-76 Deanfield  UCL

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Lifetime CVD Reduction - Investing In Your Arteries!

  • Lifelong exposure to CV risk factors, leads to

atherosclerosis and clinical events

  • The key is to sustain broad, even modest,

lowering of risk factors from early to leverage gains

  • Never too Late, Never too Early!!!!

Deanfield  UCL

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ESC  Munich 2018

CV RFs Drive Multiple Diseases

Obesity Stress BP Smoking Systemic Inflammation

 Ageing

Diabetes Stroke CVD Cancer Cholesterol Oxidative Stress Dementia A Fib.

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ESC  Munich 2018

Impact of Periodontitis Treatment on Glucose Control, Vascular and Renal Function in T2DM

Source: D’Aiuto Lancet Diabetes 2018

In UK population ▪ Severe in 5-10% ▪ Mild/mod. in 40%

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Fasting-mimicking diet and markers/risk factors for aging, T2DM, cancer, and CVD

Source: Wei et al., Sci. Transl. Med. 9, eaai8700 (2017) Deanfield  UCL

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Drug Treatments: GLP1-RA on Obesity

Source: O’Neil et al, Lancet 2018; 392: 637–49 Deanfield  UCL

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New Era for CVD Management in Diabetes

▪ Real opportunity to improve outcomes in millions

  • f diabetic patients using novel therapies

▪ Even bigger imperative to intervene early in populations to slow / prevent pathway to diabetes ▪ Collateral gains on broad range of diseases that are part of ‘unhealthy’ ageing

Diabetologists Cardiologists

Deanfield  UCL