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

Deanfield  UCL

▪ 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

Disclosures

Deanfield  UCL

New Approach to T2DM, Obesity & CV Risk Is Essential

T2DM is a new world epidemic

Deanfield  UCL

Source: Diabetes Atlas Third Edition, International Diabetes Federation (IDF)

Global Incidence of T2DM by 2025

Diabetes is the world’s THIRD MOST POPULOUS country with > 438million by 2025

Deanfield  UCL

CV Consequences of T2DM

A 50-year old with T2DM but no CVD Is ~6 years younger at time of death

Men with T2DM

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

Non-vascular deaths

Source: (L) Seshasai et al, N Engl J Med 2011; 364:829-41; (R): Sabatine MS, et al. Lancet Diab Endocrinol.

10.1016/S2213-8587(17)30313-3

T2DM doubles the risk of CV events

T2DM No T2DM

FOURIER Trial

Deanfield  UCL 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 Non-diabetic 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

The ticking clock:  CV risk before  glucose (Nurses’ Health Study)

Consequences of inflammation in obesity: adipose tissue

Calorie-dense food

Adipocyte

Lean adipose tissue Obesity adipose tissue

M1 ATM M2 ATM Hypertrophic adipocyte

↑IL 6, ↑ TNFα, ↑ IL-1β CCL2, CCL5, CXCL5

M2 ATM

↑Endothelial permeability, plaque development, atherosclerosis

CVD Systemic inflammation

↓Cholesterol metabolism, ↑glucose production, insulin resistance ↓Insulin secretion

T2DM

↓Glucose uptake, insulin resistance

Source: Yao L, et al. J Immunol Res 2014;2014:181450. CCL, chemokine (C-C motif) ligand; CXCL5, chemokine (C-X-C motif) ligand 5; IL, interleukin; TNFα, tumour necrosis factor alpha; M1 ATM, classically activated adipose tissue macrophages; M2 ATM, alternatively activated adipose tissue macrophages.

Deanfield  UCL

Deanfield  UCL

T2DM is a new world epidemic Weight loss can reverse T2DM and reduce CV Risk

New Approach to T2DM, Obesity & CV Risk Is Essential

DIRECT Trial: Remission of T2DM by Sustained Weight Loss

Deanfield  UCL

Source: Lean, M et al, Lancet Diabetes Endocrinol 2019; S2213-8587(19)30068-3

Deanfield  UCL Source: Reges et al. JAMA. 2018;319:279–90

Bariatric surgery reduces CV mortality

Laparoscopic banding

1 2 3 4 5 6 7 8 % cumulative mortality 1 2 3 4 5 6 7 8 9 10 11 Years Nonsurgical Laparoscopic banding

Roux-en-Y gastric bypass

1 2 3 4 5 6 7 8 % cumulative mortality 1 2 3 4 5 6 7 8 9 10 11 Years Nonsurgical Roux-en-Y gastric bypass

8,385 pts (65.5% women, BMI 40.6, median age 46 yrs) / 25,155 pts controls

Deanfield  UCL

• Average age: 46
• 79% women
• Average BMI – 38.4kg/m2

66% of people on AM833 + semaglutide 2.4 mg achieved >15% weight loss in 20 weeks

STEP 4 trial semaglutide sc AM833 & semaglutide phase I trial

Weight loss with semaglutide

Sources: Kushner et al. Obesity 2020;28:1050–61; Novo Nordisk. Investor Presentation. June 2020. Available here

Randomisation

% change in body weight Time since initiation (weeks)

Placebo: -5.2% Semaglutide: -18.2% 10.5%

• 2
• 4
• 6
• 8
• 10
• 12
• 14
• 16
• 18
• 20

0 4 8 12 16 20 24 28 36 44 52 60 68 % change in body weight

Mean baseline: 95.1 kg

Weeks

• 20
• 18
• 16
• 14
• 12
• 10
• 8
• 6
• 4
• 2

4 8 12 16 20

• 9.5%
• 17.1%

AM833 0.16 mg sema 2.4 mg AM833 0.3 mg sema 2.4 mg AM833 0.6 mg sema 2.4 mg AM833 1.2 mg sema 2.4 mg AM833 2.4 mg sema 2.4 mg sema 2.4 mg

Deanfield  UCL

SELECT: GLP-1RA in high CVD risk non-diabetics

Semaglutide s.c. 2.4 mg once-weekly Placebo s.c. once-weekly Event driven

1,225 first MACEs

Randomisation (1:1) N=17,500 patients Male or female ≥45 years of age BMI ≥27

Prior MI Prior stroke PAD

Primary endpoint: Time from randomisation to first occurrence of a composite endpoint consisting of either:

• CV death
• Non-fatal myocardial infarction
• Non-fatal stroke

Deanfield  UCL

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

Deanfield  UCL

Lifetime management of CV Risk T2DM is a new world epidemic Weight loss can reverse T2DM and reduce CV Risk

New Approach to T2DM, Obesity & CV Risk Is Essential

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

Obesity at 2 years predicts status at 35 years…

Deanfield  UCL Source: Twig G et al, NEJM 2016;374:2430-40

BMI during adolescence and CV mortality

Deanfield  UCL

0.72 0.70 0.68

NW OW-2009 OW-1999 OW-1989 OW-1982

11% 27% 67%

childhood 36 years 64 years

Linear beta: 0.01 (0.004, 0.015) p<0.001 cIMT (mm)

Exposure to adiposity and cIMT

0.71 0.69 0.67

Never lost weight N=682 Lost & gained N=152 Always NW N=311

cIMT (mm)

Weight loss and cIMT

P<0.001 P=0.002

Source: Charakida, Lancet Diabetes 2014;8:648-654

Exposure to adiposity and cIMT Weight loss and cIMT

MRC (UK) 1946 birth cohort

cIMT (mm)

cIMT (mm)

MRC Unit for Lifelong Health and Aging – National Survey of Health and Development (NSHD)

The NSHD, the oldest of British birth cohort studies, is unique in having data from birth to age 65 years on the health and social circumstances of a representative sample (N=5362)

Deanfield  UCL Source: Li et al. Lancet Diabetes Endocrinol 2014;2:474–80

Weight loss in pre-diabetes reduces long-term incidence of cardiovascular mortality

25 5 10 15 20 2 4 6 8 10 12 14 16 18 20 22 23

CV disease mortality: HR 0.59 (95% CI: 0.36; 0.96), p=0.033 Control Intervention

Years CVD mortality in proportion

• f participants (%)

Source: INTERHEART Lancet 2004

Prevention: Investing In Your Arteries!

Age (yrs) 20 40 60 Foetus

9 RFs accounted for 90% of MI in men and 94% in women Clinical Events

Deanfield  UCL

30 50 10 £632 pm £821 pm £1,142 pm £1,923 pm £500,000 pension pot Savings Strategy

Opportunity for Personalised Medicine: Adiposity has a THRESHOLD effect on risk of T2DM rather than a cumulative effect over time

• Mendelian

randomization (lifelong exposure): Diabetes OR: 1.26 (1.24-1.28) per 1 Kg/m2 Δ BMI

• Measured BMI

(observational): Diabetes OR: 1.22 (1.21-1.23) per 1 Kg/m2 Δ BMI

2 4 6 8 10 12 14 16 18 20 Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5 Diabetes (%) BMI Quintiles

Comparison of effect of BMI on risk of diabetes

• bservational analysis

Mendelian randomization BMI 21.8 BMI 24.6 BMI 26.7 BMI 29.2 BMI 24.7

Observational analysis

Deanfield  UCL

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