patient with Diabetes and ACS Professor Kausik Ray (UK) BSc(hons), - PowerPoint PPT Presentation

The Clinical Unmet need in the patient with Diabetes and ACS Professor Kausik Ray (UK) BSc(hons), MBChB, MD, MPhil, FRCP (lon), FRCP (ed), FACC, FESC, FAHA

Disclosures • Kausik Ray has participated in • Advisory Boards for Sanofi/ Regeneron, Amgen, Pfizer, Roche, MSD, Kowa, BI, Takeda; • Acted as a speaker for AZ, Pfizer, Sanofi Regeneron, Amgen, Kowa, Algorithm, Cipla, BI, Takeda • Received research grant support from Sanofi/Regeneron, Pfizer, Amgen & MSD; CME lectures at Symposia for Sanofi/Regeneron, Amgen, Pfizer, AZ & MSD; • NLI/ SC member for Odyssey- (Sanofi/ Regeneron), Roche; PI for ORION 1 (Medicines Company), Cerenis, Lilly, Esperion, Kowa, AZ, Resverlogix

Diabetes is a global public health challenge and outcomes remain poor compared to those without Diabetes

Prevalence of diabetes in 2030 2010 2030 Total number of people with 285 million 438 million diabetes (age 20-79) Prevalence of diabetes (age 20- 6.6 % 7.8 % 79) IDF diabetes atlas, 4th edition, 2009

Diabetes doubles the risk of vascular events Emerging Risk Factors Collaboration Outcome No. of cases HR (95% CI) Coronary heart disease 26,505 2.00 (1.83 – 2.19) Coronary death 11,556 2.31 (2.05 – 2.60) Non-fatal MI 14,741 1.82 (1.64 – 2.03) Cerebrovascular disease Ischaemic stroke 3799 2.27 (1.95 – 2.65) Haemorrhagic stroke 1183 1.56 (1.19 – 2.05) Unclassified stroke 4973 1.84 (1.59 – 2.13) Other vascular deaths 3826 1.73 (1.51 – 1.98) 2 1 2 4 Hazard ratio (diabetes vs no diabetes) CI, confidence interval; HR, hazard ratio; MI, myocardial infarction. Sarwar N, et al. Lancet . 2010;375:2215 – 2222.

Estimated life years lost among those with Diabetes Seshasai, NEJM. 2011 ;364(9): 829-841

Life expectancy is reduced by ~12 years in diabetes patients with previous CVD* Modelling of years of life lost by disease status of participants at baseline compared with those free of diabetes, stroke and MI *Male, 60 years of age with history of MI or stroke The Emerging Risk Factors Collaboration. JAMA . 2015;314:52 7

7 Year Risk of Cardiovascular death, MI, documented unstable angina requiring rehospitalization , coronary revascularization (≥30 days), or stroke in IMPROVE IT LDL-C ~68mg/dl LDL-C~53mg/dl 45,5 40 34,7 32,7 30,8 30,2 Overall DM No DM Cannon Et al NEJM 2015

Reducing CV risk in T2D may need a multifactorial approach Control of dyslipidaemia Targeting additional pathways Antihypertensive Antiplatelet (inflammation,  CV therapy therapy complement activation, risk Activated vasculature Reverse cholesterol Weight loss Glycaemic transport and lifestyle control intervention* CV, cardiovascular; T2D, Type 2 Diabetes. *Includes smoking cessation. Rydén L, et al. Eur Heart J . 2013;34:3035 – 3087.

What else is perturbed and which could be a target for therapy ?

Perturbed Vasculature Ray JACC 2005

A perturbed vasculature predicts recurrent events Post ACS Ray AJC 2006

The risk from a perturbed vasculature may be attenduated by treaments that reduce LDL-C and inflammtion Ray AJC 2006

The presence of heightened inflammation or a perturbed vascular is associated with greater risk in those with DM vs those without – OPUS TIMI 16 Ray EHJ 2012

Validation of the greater impact of inflammation on adverse outcomes among those with DM vs those without DM in TACTICS-TIMI 18 Ray EHJ 2012

Potential mechanism of increased risk is an interaction between dysglycaemia and inflammation in DM Ray EHJ 2012

Targeting HDL function

Is HDL-C causal? No Estimate of the association of genetically raised LDL cholesterol or HDL cholesterol and risk of myocardial infarction using multiple genetic variants as instruments Odds ratio (95% CI) per SD increase in Odds ratio (95% CI) per SD increase in plasma lipid based on observational plasma lipid conferred by genetic epidemiology* score † LDL cholesterol 1.54 (1.45 – 1.63) 2.13 (1.69 – 2.69), p=2x10 – 10 HDL cholesterol 0.62 (0.58 – 0.66) 0.93 (0.68 – 1.26), p=0.63 *Observational epidemiology estimates derived from more than 25,000 individuals from prospective cohort studies; †LDL genetic score consisting of 13 SNPs, and HDL genetic score consisting of 14 SNPs SNP, single nucleotide polymorphism Voight BF, et al. Lancet 2012;380:572 – 80

Is low HDL-C a risk marker? Yes 5-year risk 12 of major Atorvastatin 10 mg CV events 10 Atorvastatin 80 mg (%) 8 6 4 2 0 Q1 Q2 Q3 Q4 Q5 (<38) (38 – <43) (43 – <48) (48 – <55) (≥55) Quintile of HDL cholesterol level (mg/dl) Number of events: 113 91 125 97 102 68 103 86 87 71 Barter P, et al. N Engl J Med 2007;357:1301 – 10

Potential atheroprotective effects of HDL Endothelial repair Anti-apoptotic Protection against oxidation Anti-inflammatory Modulation of Antithrombotic endothelial function HDL Cholesteryl ester Cholesterol donor Transport

HDL cholesterol efflux capacity and incident cardiovascular events Atherosclerotic cardiovascular disease Hazard ratio 10 Participants Adjusted Unadjusted with event P=0.002 by log-rank test (%) 8 Reference Reference Q1 0.71 (0.46 – 1.10) Q2 0.74 (0.48 – 1.13) 6 Q3 0.49 (0.31 – 0.79) 0.42 (0.26 – 0.68) 4 0.33 (0.19 – 0.55) Q4 0.44 (0.27 – 0.73) 2 0 0 1 2 3 4 5 6 7 8 9 Year Rohatgi A, et al. N Engl J Med 2014;371:2383 – 93

Other Potential Pathways

Relationship of Proteinuria, eGFR and Mortality 3.84 2.62 Hazard ratio 1.68 3.04 3.84 1.7 2.62 2.08 1.34 1.3 3.04 1.7 1.68 2.08 1.34 1.33 2.26 <45 1.55 1 1 45-60 eGFR >60 none trace 1 + >2+ Proteinuria Tonelli et al. CARE investigators. BMJ 2005. In Print

Where is the highest risk / Unmet need? • Patients with ACS • Patients with ACS and DM • Patients with ACS, DM and low HDL • Very high event rate!

Apabetalone Biomarker Changes Accompanied by MACE Reduction in Phase 2 Studies MACE: Major Adverse Cardiac Events Note: Patients were censored at 30 days including: death, after the last dose of study medication. myocardial infarction, stroke, coronary Source: RVX data on file – ASSURE and revascularization, SUSTAIN Safety Population. Log-Rank test for between group comparison hospitalization for acute coronary syndrome or heart failure 25

BETonMACE CV Outcomes Study Design Primary Endpoint Key inclusion criteria • Time from randomization to the first occurrence T2DM of adjudication-confirmed triple MACE defined o HbA1c > 6.5% or history of diabetes medications • as a single composite endpoint of CV Death or CAD event 7 days - 90 days prior to Visit 1 Non-fatal MI or Stroke. o MI, UA or PCI • HDL < 1.04 for males and < 1.17 for females Secondary Endpoint Time from randomization to the first occurrence Primary Objective of adjudication-confirmed MACE including To evaluate if treatment with apabetalone as compared revascularization and UA to placebo increases time to the first occurrence of triple Changes in apoA-I, apoB, LDL-C, HDL-C, and MACE. Triple MACE is defined as a single composite TG endpoint of CV death or non-fatal MI or stroke. Changes in HbA1c, fasting glucose, and fasting insulin Changes in ALP and eGFR 26

BETonMACE CV Outcomes Study Design atorvastatin safety follow-up 2,400 + subjects apabetalone 200mg daily + standard of care and • double blinded rosuvastatin placebo + standard of care safety follow-up • 1-2 week statin run-in run-in standard of care includes 20-80 mg atorvastatin or 10-40 mg rosuvastatin 1-2 weeks treatment duration up to 104 weeks 4-16 weeks screening randomization (1:1) end of treatment The study is an event-based trial and continues until 250 events have occurred.

Summary • T2D is a major public health challenge • CV events are highest in patients with T2D and ACS • Beyond current therapies targeting several novel pathways known to be perturbed post ACS may offer novel solutions to current unmet need