Importance of protection and prevention in cardiorenal disease John Deanfield, MD London, United Kingdom June 15, 2019 - Budapest, Hungary
Protection and Prevention in Diabetic Cardio-renal Disease Professor John Deanfield - University College London, UK Budapest ERA EDTA - 15 June 2019 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
Need for Joint Approach…CVD and CKD Go Together! “ It is observable, that the hypertrophy of the heart seems, in some degree, to Diabetes have kept pace with the advance of disease in the kidneys; for in by far the majority of cases, when the heart was increased, the hardness and contraction of the kidney bespoke the CKD CVD probability of long continuance of the disease.” - R Bright, 1836 Deanfield UCL
Cardio-renal Disease in Diabetes Novel treatments can improve cardio-renal outcomes in patients with diabetes Prevention is important as long term exposure to risk factors drives cardio-renal disease Leveraged gain from early intervention on common pathways to disease Emerging early role for new drugs? Never Too Late…Never Too Early…!! Deanfield UCL
Evidence Based Cardiorenal Risk Reduction • Statins • BP Lowering • Metformin • ACEi / ARB GLP1-RA SGLT2-i 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
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 (%) p =0.02 for superiority HR: 0.87 1 5 Patients with event (%) (95% CI: 0.78 ; 0.97) Placebo 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) Source: Marso SP et al. N Engl J Med 2016;375:311 – 322 Source: Marso SP et al. N Engl J Med 2016;375:1834 – 1844 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
Renal Benefit from GLP-1RA and SGLT-2i Deanfield UCL Source: Newman JD, et al, J Am Coll Cardiol 2018; 72(15):1856-69
REWIND 9,900 individuals with T2DM and eGFR of Cumulative (%) ≥ 15mL/ min; Dulaglutide v Placebo; > two thirds primary CV prevention Time Since Randomisation (yrs) Deanfield UCL Source: Hertzel C Gerstein, Lancet x.doi.org/10.1016/S0140-6736(19)31150-X
Exciting New Era for CVD Management in DM Diabetologists Cardiologists Primary Care Nephrology Deanfield UCL
A Thought… “Why just strive to treat a disease like Diabetes better when you could prevent it?” Deanfield UCL
Diabetes Epidemic : Risk Factors start Early! 2015 2040 Source Bjerregaard et al, N Engl J Med 2018;378:1302-12 Source: IDF Diabetes Atlas. 7th edn. 2015 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 Deanfield UCL
Primary Care-led Weight Management For Remission of T2DM (DiRECT) > 10kg Weight Loss 64%Remission Source: Lean, M et al, Lancet 2018; 391: 541 – 51 Deanfield UCL
Impact of GLP1-RA on Obesity Source: O’Neil et al, Lancet 2018; 392: 637– 49 Deanfield UCL
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
SELECT: GLP1-RA in high CVD risk Non Diabetics 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 Deanfield UCL
CV RFs Drive Multiple Diseases Through Common Pathways Stress BP Obesity Cholesterol Smoking Systemic Inflammation Oxidative Stress Ageing Dementia Stroke Cancer Diabetes CKD CVD Deanfield UCL
Impact of Periodontitis Treatment on Glucose Control, Vascular and Renal Function in T2DM In UK population ▪ Severe in 5-10% ▪ Mild/mod. in 40% Source: D’Aiuto Lancet Diabetes 2018 Deanfield UCL
How Early Should Prevention Start? “Poor Start in Life” 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 CV Mortality Diabetes and Hypertension Deanfield UCL Source: Twig G et al, NEJM 2016;374:2430-40
Cardio-renal Disease in Diabetes: Protection & Prevention New era for treatment of cardio-renal disease Earlier management is needed to target disease in the population Emerging role for new drugs and lifestyle in pre-clinical disease Deanfield UCL
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
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