Potential for New Concepts and Tools Monday 31 August 2020 - PowerPoint PPT Presentation

Changing Paradigm in Prediabetes and CVD: Potential for New Concepts and Tools Monday 31 August 2020 Professor John Deanfield, UCL Deanfield  UCL

Disclosures ▪ Received CME honoraria and/or consulting fees from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk, Bayer ▪ Research grants from BHF, MRC(UK), NIHR, PHE, MSD, Pfizer, Aegerion, Colgate, Roche ▪ Member of SOUL and SELECT Study Steering Committees for Novo Nordisk ▪ Board Director of Cydar Ltd ▪ No conflicts of interest for this presentation Deanfield  UCL

New Approach to T2DM, Obesity & CV Risk Is Essential T2DM is a new world epidemic Deanfield  UCL

Global Incidence of T2DM by 2025 Diabetes is the world’s THIRD MOST POPULOUS country with > 438million by 2025 Source: Diabetes Atlas Third Edition, International Diabetes Federation (IDF) Deanfield  UCL

CV Consequences of T2DM Men with T2DM FOURIER Trial 7 6 T2DM Vascular deaths 5 Years of life lost Non-vascular deaths 4 No 3 T2DM 2 1 0 0 40 50 60 70 80 90 Age (years) A 50-year old with T2DM but no CVD T2DM doubles the risk of CV events Is ~6 years younger at time of death Source: (L) Seshasai et al, N Engl J Med 2011; 364:829-41; (R): Sabatine MS, et al. Lancet Diab Endocrinol. Deanfield  UCL 10.1016/S2213-8587(17)30313-3

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 Non-diabetic Risk of event Risk of event Diabetic throughout prior to after DM at B/L the study DM diagnosis diagnosis Deanfield  UCL Source: Hu et al, Diabetes Care 2002; 25: 1129-1134

Consequences of inflammation in obesity: adipose tissue M2 ATM M1 ATM Adipocyte Hypertrophic adipocyte M2 ATM Calorie-dense food Lean adipose tissue Obesity adipose tissue ↑IL 6, ↑ TNFα, ↑ IL - 1β Systemic inflammation CCL2, CCL5, CXCL5 ↑Endothelial permeability, ↓Cholesterol metabolism, ↓Glucose uptake, ↓Insulin secretion ↑glucose production, plaque development, insulin resistance atherosclerosis insulin resistance CVD T2DM Source: Yao L, et al. J Immunol Res 2014;2014:181450. Deanfield  UCL CCL, chemokine (C-C motif) ligand; CXCL5, chemokine (C-X-C motif) ligand 5; IL, interleukin; TNF α, tumour necrosis factor alpha; M1 ATM, classically activated adipose tissue macrophages; M2 ATM, alternatively activated adipose tissue macrophages.

New Approach to T2DM, Obesity & CV Risk Is Essential T2DM is a new world epidemic Weight loss can reverse T2DM and reduce CV Risk Deanfield  UCL

DIRECT Trial: Remission of T2DM by Sustained Weight Loss Source: Lean, M et al, Lancet Diabetes Endocrinol 2019; S2213-8587(19)30068-3 Deanfield  UCL

Bariatric surgery reduces CV mortality 8,385 pts (65.5% women, BMI 40.6, median age 46 yrs) / 25,155 pts controls Laparoscopic banding Roux-en-Y gastric bypass 8 8 7 7 Nonsurgical Nonsurgical 6 6 % cumulative mortality % cumulative mortality 5 5 4 4 3 3 2 2 Roux-en-Y gastric Laparoscopic 1 1 bypass banding 0 0 0 1 2 3 4 5 6 7 8 9 10 11 0 1 2 3 4 5 6 7 8 9 10 11 Years Years Source: Reges et al. JAMA. 2018;319:279 – 90 Deanfield  UCL

Weight loss with semaglutide AM833 & semaglutide phase I trial STEP 4 trial semaglutide sc Randomisation 0 % change in body weight 0 Mean baseline: -2 -2 95.1 kg % change in body weight -4 Placebo: -5.2% -4 -6 -6 -8 -8 -9.5% -10 -12 -10 -14 -12 10.5% -16 -14 -17.1% -18 -16 -20 0 4 8 12 16 20 -18 Semaglutide: -18.2% Weeks -20 AM833 0.16 mg AM833 0.3 mg AM833 0.6 mg 0 4 8 12 16 20 24 28 36 44 52 60 68 sema 2.4 mg sema 2.4 mg sema 2.4 mg AM833 1.2 mg AM833 2.4 mg Time since initiation (weeks) sema 2.4 mg sema 2.4 mg sema 2.4 mg • Average age: 46 66% of people on AM833 + semaglutide 2.4 mg • 79% women achieved >15% weight loss in 20 weeks • Average BMI – 38.4kg/m 2 Deanfield  UCL Sources: Kushner et al. Obesity 2020;28:1050 – 61; Novo Nordisk. Investor Presentation. June 2020. Available here

SELECT: GLP-1RA in high CVD risk non-diabetics Semaglutide s.c. 2.4 mg once-weekly N=17,500 patients Male or female ≥45 years of age Placebo s.c. once-weekly BMI ≥ 27 Event driven 1,225 first MACEs Randomisation (1:1) Primary endpoint: Time from randomisation to first occurrence of a Prior Prior composite endpoint consisting of either: PAD MI stroke • CV death • Non-fatal myocardial infarction • Non-fatal stroke Deanfield  UCL

A new thought… We should intervene early to prevent both diabetes and CVD… Deanfield  UCL

New Approach to T2DM, Obesity & CV Risk Is Essential T2DM is a new world epidemic Weight loss can reverse T2DM and reduce CV Risk Lifetime management of CV Risk Deanfield  UCL

Obesity at 2 years predicts status at 35 years… Deanfield  UCL Source: Ward et al, N Engl J Med 2017;377:2145-53

BMI during adolescence and CV mortality Deanfield  UCL Source: Twig G et al, NEJM 2016;374:2430-40

MRC (UK) 1946 birth cohort Exposure to adiposity and cIMT Exposure to adiposity and cIMT 11% 27% 67% childhood 36 years 64 years 0.72 Linear beta: 0.01 (0.004, 0.015) p<0.001 cIMT (mm) cIMT (mm) 0.70 0.68 MRC Unit for Lifelong Health and Aging – National Survey of Health and NW OW-2009 OW-1999 OW-1989 OW-1982 Development (NSHD) Weight loss and cIMT Weight loss and cIMT The NSHD, the oldest of British birth cohort studies, is P<0.001 unique in having data from birth to age 65 years on the P=0.002 cIMT (mm) 0.71 health and social circumstances of a representative cIMT (mm) sample (N=5362) 0.69 0.67 Never lost weight Lost & gained Always NW N=682 N=152 N=311 Deanfield  UCL Source: Charakida, Lancet Diabetes 2014;8:648-654

Weight loss in pre-diabetes reduces long-term incidence of cardiovascular mortality 25 CV disease mortality: HR 0.59 CVD mortality in proportion (95% CI: 0.36; 0.96), p =0.033 Control 20 of participants (%) 15 Intervention 10 5 0 0 2 4 6 8 10 12 14 16 18 20 22 23 Years Deanfield  UCL Source: Li et al. Lancet Diabetes Endocrinol 2014;2:474 – 80

Prevention: Investing In Your Arteries! 9 RFs accounted for 90% of MI in men and 94% in women Clinical Events Foetus 0 10 20 30 40 50 60 Age (yrs) £500,000 £632 £821 £1,142 £1,923 Savings Strategy pension pot pm pm pm pm Deanfield  UCL Source: INTERHEART Lancet 2004

Opportunity for Personalised Medicine: Adiposity has a THRESHOLD effect on risk of T2DM rather than a cumulative effect over time Comparison of effect of BMI on risk of diabetes • Mendelian 20 BMI 24.7 randomization observational analysis Observational analysis Mendelian randomization 18 (lifelong exposure): 16 Diabetes OR: 1.26 14 Diabetes (%) (1.24-1.28) per 1 12 Kg/m 2 Δ BMI 10 BMI 29.2 8 • Measured BMI BMI 26.7 6 4 BMI 24.6 (observational): BMI 21.8 2 Diabetes OR: 1.22 0 (1.21-1.23) per 1 Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5 Kg/m 2 Δ BMI BMI Quintiles

Changing Paradigm for Cardiometabolic Risk Management Lowering of CV risk in established T2DM or CVD is possible but not enough Substantial weight loss can be achieved by diet, surgery and new drugs (GLP1-RA) Ongoing trials are testing impact on CV outcome in obese patients with CV RFs/CVD Early, intervention can personalise strategies for prevention of T2DM and lifetime reduction of CVD Deanfield  UCL