The clinical landscape for T2DM and CVD: Extending the opportunities John E Deanfield, MD London, United Kingdom Cardio Diabetes Master Class February 22-23, 2019 - Barcelona, Spain
The Clinical Challenge 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
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
Evidence Based CV Risk Reduction • Statins • BP Lowering • Metformin GLP1-RA SGLT2-i PACE Dubai 2018
Cost-effectiveness Adverse Events Liraglutide Placebo p -value* Any adverse event <0.001 0.01 Serious adverse event Severe adverse event 0.22 <0.001 Nausea Vomiting <0.001 <0.001 Diarrhoea Lipase increased † 0.43 Abdominal pain 0.03 Decreased appetite 0.01 0.002 Abdominal discomfort Proportion of patients (%)
Guidelines 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
Draft ADA and EASD consensus guideline ASCVD predominates Heart failure (HF) predominates SGLT2-i with evidence GLP-1 RA with SGLT2-i with proven OR of reducing HF in CVOT GLP-1 RA with OR proven CVD CVD benefit if eGFR trials if eGFR adequate 2- proven CVD benefit 1 benefits 1 adequate 1-2 3 If HbA 1c above target If HbA 1c above target • If further intensification is required or patient is now unable to tolerate GLP-1 RA Avoid TZD and/or SGLT2-i, choose agents demonstrating CV safety: Choose agents demonstrating CV safety: • • Consider adding the other class with proven CVD benefit Consider adding the other class with proven CVD benefit 1 • DDP-IVi if not on GLP-1 RA • DDP-IVi (not Saxagliptin) if not on GLP-1 RA • Basal insulin 4 • Basal insulin 4 • TZD 5 • SU 6 • SU 6 ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular; CVD, cardiovascular disease; DPP-IVi, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HF, heart failure; SGLT2-i, sodium-glucose cotransporter-2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedione. 1. SGLT2-i = Empagliflozin preferred, GLP-1 RA = Liraglutide preferred. Proven CVD benefit means it has label indication of reducing CVD events. Please see hierarchy of evidence in manuscript for CVD benefits for agents within the GLP-1 RA and SGLT2-i class; 2. Be aware that SGLT2-i vary by region and individual agent with regard to indicated level of eGFR for initiation and continued use; 3. Both Empagliflozin and Canagliflozin have shown reduction in HF in CVOT trials; 4. Degludec or U100 Glargine have demonstrated CVD safety; 5. Low dose may be better tolerated though less well studied for CVD effect; 6. Choose later generation SU with lower risk of hypoglycaemia
Implementation 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
How to Organize Best Care for Patients with Diabetes? Diabetologists, Cardiologists, Nephrologists, Primary Care physicians need to work together in care plan Deanfield UCL
Barriers to Best Care • Cardiologists ➢ General medicine poor ➢ Uncomfortable with Hypos ➢ Don ’ t like injectables! • Diabetologists ➢ Disenfranchised by cardiologists ➢ Lack of effective CVD treatments until now ➢ Complex glucose centric guidelines ESC Munich 2018
Investing In Your Arteries! Genetic Environmental Lots of risk in front : lots of lost opportunities behind! Diabetologists should be Preventative Cardiologists! Clinical Events Foetus 0 20 40 60 April 19 Age (yrs) Source: INTERHEART Lancet 2004
Personalised Nutrition by Prediction of Glycemic Responses Deanfield UCL Source: Zeevi Cell 2015; 163: 1079-1094
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
“Sick Individuals and Sick Populations” • Two strategies for prevention: The ‘ high risk ’ approach - seeking to protect susceptible individuals The ‘ population ’ approach - to control the underlying causes of incidence Geoffrey Rose, CBE (April 1926 – November 1993) Source: Rose, Int. J Epidemiol,1985;14:32-38 ESC Munich 2018
The Public Health Challenge Deanfield UCL
Diabetes is a growing epidemic 1:10 people in the world will have diabetes by 2035…. http://blogs.reuters.com/data-dive/2013/11/15/the-world-diabetes-epidemic-in-charts/
CVD: It’s Not All Over! Source: CVD Statistics – BHF UK Factsheet – February 2018
CVD Prevention: Challenge! “The human race has had long experience and a fine tradition in surviving adversity; we now face a task for which we have little experience, the task of surviving prosperity” Source: Alan Gregg (1890-1957), Rockefeller Foundation Deanfield UCL
Obesity: Clear and Present Danger “ The commonest Instruments of suicide are a knife and fork” Martin Fischer
Jamie Oliver’s Healthy School Meals Who is responsible for our health? Child? Parents? Government? Doctors? Advocates for political/ Societal change
“The Next Five Years for the NHS” : Simon Stevens, Chief Executive NHS England “First, as a nation it’s time to get our act together on prevention…we’ve got a choice. Condemn our children to a rising tide of avoidable diabetes, cardiovascular disease, cancer? And burden taxpayers with an NHS bill far exceeding an extra £8 billion by 2020? Or take wide ranging action – as families, as the health service, as government, as industry. It’s a no brainer – pull out all the stops on prevention, or face the music.” Source: Speaking at a conference on 18 May 2015 Moscow PACE 2018
Obesity and CV Disease: Policy Interventions
Take Home Messages ➢ Incorporate evidence based treatments in our care ➢ Work with colleagues and think about T2DM/CV Risk ➢ Prevention opportunities – primary and secondary ➢ Advocates for political and societal changes
Final Thought… “It should be the function of medicine to have people die young as late as possible” - Ernest L. Wynder M.D Deanfield UCL 2018
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