Shifting gears in CVD & T2DM: What is the rationale for new - - PowerPoint PPT Presentation

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 Class

November 16 - 17, 2018 - Dubai, UAE

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

Shifting Gears in CVD and T2DM: What Is The Rationale For New Diabetes Interventions in the Course of CVD?

Professor John Deanfield, UCL Dubai, November 2018

PACE Dubai 2018

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

PACE Dubai 2018

PACE Dubai 2018

Major Diabetes Complications in USA

PACE Dubai 2018

CVD Admissions Hyperglycaemic Deaths

PACE Dubai 2018

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

• Management should be targeted at

reducing/delaying CV complications in patients with T2DM with and without clinical CVD

• Most cardiologists have focused efforts
• n ‘traditional’ CVRFs and not on glucose

lowering

PACE Dubai 2018

Treatment Goals in T2DM in 2018 and beyond…

Source: Goldner MG, JAMA 1971,218, 1400-10

PACE Dubai 2018

CARDS: Cumulative Hazard for MI and CV Death

Source: Colhoun Lancet 2004;364:685–696

Atorvastatin

Cumulative Hazard (%) Relative Risk -37% (95% CI: -52, -17) P=0.001

Years

Placebo

5 10 15 1 2 3 4 4.75

PACE Dubai 2018

Benefit of Different Interventions per 200 Diabetes Patients Treated for 5 years

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

Using traditional Glucose lowering treatments Per 0.9% lower HbA1c Per 4mm Hg lower SBP Per 1mmol/L lower LDL-C CV Events 5.0 0.0

• 5.0
• 12.5
• 15.0
• 20.0
• 10.0
• 8.2
• 2.9

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

Diabetes Treatment for CVD Reduction

SGLT-2 Inhibitors GLP-1R Agonsits

PACE Dubai 2018

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

Dapagliflozin and CV Outcomes: DECLARE Study

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

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

Source: A Hernandez for the Harmony Outcomes committees and investigators* et al Lancet 2018; 392: 1519–29

Albiglutide and CV Outcomes : HARMONY Trial

Cardiovascular Death Myocardial Infarction Stroke Composite of All Cause of Death

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

Renal Benefit from GLP-1RA and SGLT-2i

PACE Dubai 2018

• Statins
• BP Lowering
• Metformin

SGLT2-i GLP1-RA

Evidence Based CV Risk Reduction

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

Source: Thomas Zelniker et al, Lancet 2018, http://dx.doi.org/10.1016/S0140-6736(18)32590-X

SGLT2i trials Composite of Major adverse CV Events

DECLARE Trial: Death from Vascular or Other Causes

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

. 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

GLP-1RAs Improve CV and Renal Outcomes Across BP and BMI

Source: Leitner an Verma :AHA 2018 Scientific Sessions

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

PACE Dubai 2018

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

PACE Dubai 2018

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?

? ?

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

?

Future CVOTs

Heart failure Nephropathy Obesity

?

A Question for you…?

“Why do we want to be brilliant at treating illnesses that we could have prevented?”

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!

Gruber J and Frakes M. J Health Econ. www.sciencedirect.com.

0.35 0.3 0.25 0.2 0.15 0.1 0.05 0.4

Proportion

• f population

1970

Year

1974 1978 1982 1986 1990 1994 1998 2002

Obesity rate Smoking rate

Decline in Smoking vs Rise in Obesity: a Trade Off?

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

BMI During Adolescence and CV Mortality

PACE Dubai 2018

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

PACE Dubai 2018

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

34% 35% 31% GAMI-pat

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

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

PACE Dubai 2018

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

PACE Dubai 2018

Healthy Lifestyle and CVD in T2DM

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

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

1225 first MACEs

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

Prior MI Prior stroke PAD

SELECT: Trial Design ,Population and Endpoint

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

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

Stomach

Intracellular space

Microvilli

Columnar epithelial cell

SNAC, Sodium 8-((2-hydroxybenzoyl)amino)octanoate monosodium

Semaglutide SNAC

New Oral Formulation of SNAC and Semaglutide

PACE Dubai 2018

New Era for CVD Management in DM: Some Thoughts

▪ In addition to BP and Cholesterol lowering, CVD and renal benefit with two new glucose lowering drug classes, SGLT2i and GLP1-RA ▪ Has already changed guidelines for DM care ▪ Novel multiple mechanisms, especially with lack of hypoglycaemia will broaden indications towards early treatment, prevention, even without DM

Diabetologists Cardiologists