The Clinical Unmet need in the patient with Diabetes and ACS

Transcription

1 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

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

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

4 Diabetes doubles the risk of vascular disease Data from 528,877 participants (adjusted for age, sex, cohort, SBP, smoking, BMI) Outcome Number of cases HR (95% CI) I 2 (95% CI) Coronary heart disease 26, ( ) 64 (54 71) Coronary death 11, ( ) 41 (24 54) Non-fatal MI 14, ( ) 37 (19 51) Cerebrovascular disease 11, ( ) 42 (25 55) Ischaemic stroke ( ) 1 (0 20) Haemorrhagic stroke ( ) 0 (0 26) Unclassified stroke ( ) 33 (12 48) Other vascular deaths ( ) 0 (0 26) BMI, body mass index; CI, confidence HR interval; (diabetes HR, vs no hazard diabetes) ratio; MI, myocardial infarction; SBP, systolic blood pressure Emerging Risk Factors Collaboration. Lancet 2010;375:2215

5 Years of life lost Diabetes is associated with significant loss of life years 7 6 Men Non-vascular deaths 7 Vascular deaths 6 Women Age (years) Age (years) 5 On average, a 50-year-old individual with diabetes and no history of vascular. disease will die 6 years earlier compared to someone without diabetes Seshasai et al. N Engl J Med 2011;364:829-41

6 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 6 The Emerging Risk Factors Collaboration. JAMA. 2015;314(1):52-60.

7 Life expectancy is reduced by 12 years in diabetes patients* with previous CV disease yrs 60 End of life No Diabetes Diabetes -6 yrs Diabetes +MI -12 yrs In this case, CV disease is represented by MI or stroke. *60 years of age. CV, cardiovascular; MI, myocardial infarction. 7 The Emerging Risk Factors Collaboration. JAMA. 2015;314:52 60.

8 Interventions that reduce cardiovascular disease Lipid lowering? Blood pressure? Glucose lowering?

9 RR reduction or hazard ratio (%) Statin therapy has a pivotal role in reducing CV risk Non-diabetes Secondary prevention Diabetes Combined High risk Trial 4S 1,2 LIPID 1,2 CARE 1,2 TNT 3 HPS 1,2 WOSCOPS 4 AFCAPS/ JUPITER 6 CARDS 7 ALLHAT-LLT 8 TexCAPS N ,001 20, , Primary prevention , Ryden et al. Eur Heart J 2007;28: Libby. J Am Coll Cardiol 2005;46: LaRosa et al. N Engl J Med 2005;352: Shepherd et al. N Engl J Med 1995;333: Downs et al. JAMA 1998;279: Ridker et al. N Engl J Med 2008;359: Colhoun et al. Lancet 2004;364: ALLHAT-LLT. JAMA 2002;288:

10 Cumulative incidence of major CV events* Time to first major cardiovascular event in patients with diabetes HR=0.75 (95% CI ) p=0.026 Atorvastatin 10 mg Atorvastatin 80 mg Relative risk reduction = 25% Time (years) *CHD death, non-fatal non-procedure-related MI, resuscitated cardiac arrest, fatal or non-fatal stroke. CV, cardiovascular Shepherd J et al. Diabetes Care 2006;29:1220

11 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, ,7 32,7 30,8 30,2 Overall DM No DM Cannon Et al NEJM 2015

12 Interventions that reduce cardiovascular disease Lipid lowering? Blood pressure? Glucose lowering?

13 10 mmhg reduction in SBP reduces all-cause mortality, macrovascular and microvascular outcomes in T2D Outcome All-cause mortality Macrovascular disease Favours BP lowering Favours control CV disease CHD Stroke Stroke Heart failure Microvascular disease Renal failure Retinopathy Albuminuria Relative risk (95% CI) Meta-analysis of 40 large scale, randomised, controlled trials of BP-lowering treatment including patients with diabetes (n=100,354 participants). 13 Emdin et al. JAMA 2015;313:

14 SBP (mmhg) ACCORD Average after 1 st year: Standard, Intensive; Delta = Int. N = Std. 0 N = Years post-randomisation Intensive Standard ACCORD Study Group. N Engl J Med 2010;362:1575

15 Primary and secondary outcomes Intensive events (%/yr) Standard events (%/yr) HR (95% CI) p Primary 208 (1.87) 237 (2.09) 0.88 ( ) 0.20 Total mortality 150 (1.28) 144 (1.19) 1.07 ( ) 0.55 CV death 60 (0.52) 58 (0.49) 1.06 ( ) 0.74 Non-fatal MI 126 (1.13) 146 (1.28) 0.87 ( ) 0.25 Non-fatal stroke 34 (0.30) 55 (0.47) 0.63 ( ) 0.03 Total stroke 36 (0.32) 62 (0.53) 0.59 ( ) 0.01 ACCORD Study Group. N Engl J Med 2010;362:1575

16 Interventions that reduce cardiovascular disease Lipid lowering? Blood pressure? Glucose lowering?

17 Effects of more- vs less-intensive control of glucose on non-fatal MI, CHD, stroke and mortality Non-fatal MI Study Odds ratio (95% CI) Weight (%) CHD Study Odds ratio (95% CI) Weight (%) UKPDS PROactive ADVANCE VADT ACCORD Overall 0.78 (0.62, 0.98) 0.83 (0.64, 1.06) 0.98 (0.78, 1.23) 0.81 (0.58, 1.15) 0.78 (0.64, 0.95) 0.83 (0.75, 0.93) UKPDS PROactive* ADVANCE VADT ACCORD Overall 0.75 (0.54, 1.04) 0.81 (0.65, 1.00) 0.92 (0.78, 1.07) 0.85 (0.62, 1.17) 0.82 (0.68, 0.99) 0.85 (0.77, 0.93) I 2 =0% (95% CI %), p=0.61 I 2 =0% (95% CI 0-53%), p= Odds Ratio Intensive therapy better Standard therapy better Stroke Study UKPDS PROactive ADVANCE VADT ACCORD Overall Odds ratio (95% CI) 0.91 (0.51, 1.61) 0.81 (0.60, 1.08) 0.97 (0.81, 1.16) 0.78 (0.47, 1.28) 1.05 (0.76, 1.46) 0.93 (0.81, 1.06) Weight (%) I 2 =0% (95% CI 0-62%), p= Intensive therapy better All-cause mortality Study UKPDS PROactive ADVANCE VADT ACCORD Overall Odds Ratio Standard therapy better Odds ratio (95% CI) 0.79 (0.53, 1.20) 0.96 (0.77, 1.19) 0.93 (0.82, 1.05) 1.09 (0.81, 1.47) 1.28 (1.06, 1.54) 1.02 (0.87, 1.19) Weight (%) I 2 =58% (95% CI 0-84%), p= Odds Ratio Odds Ratio Intensive therapy better Standard therapy better Intensive therapy better Standard therapy better Ray KK et al. Lancet 2009;373:1765. *Included non-fatal MI and death from all-cardiac mortality; Included only non-fatal strokes

18 Number of CV events* prevented Cardiovascular risk reduction requires multiple interventions including blood pressure and lipid management Benefit of different interventions per 200 diabetic patients treated for Per 4 mmhg lower SBP -12,5 years Per 1 mmol/l lower LDL-C -8,2 Per 0.9% lower HbA1c -2,9 *Comprised non-fatal MI, CHD, stroke and all-cause mortality Ray KK et al. Lancet 2009;373:1765

19 DDP 4 inhibitors do not reduce CVD Abbas A & Ray KK. Diabetes Obesity Metabolism 2015

20 Other novel treatments for DM SGLT2 (empagliflozin) only reduced CV death and HF hospitalization in stable chronic patients GLP1 agonist (liraglutide) only reduced CV death in stable CAD patients GLP-1 lixisenatide did not affect CV death NF MI or stroke composite in people with DM after an ACS

21 Other novel treatments for reducing CVD PCSK9 monoclonal Ab Direct inhibition of IL-1 beta (inflammation) CANTOS trial

22 LDL Cholesterol (mg/dl) LDL Cholesterol Placebo % mean reduction (95%CI 58-60), P< Absolute reduction: 56 mg/dl (95%CI 55-57) Evolocumab (median 30 mg/dl, IQR mg/dl) Weeks

23 CV Death, MI, Stroke, Hosp for UA, or Cor Revasc 16% 14% 12% 10% 8% 6% 4% 2% 0% Primary Endpoint Hazard ratio 0.85 (95% CI, ) P< % Placebo Months from Randomization Evolocumab %

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

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

26 Perturbed Vasculature Ray JACC 2005

27 A perturbed vasculature predicts recurrent events Post ACS Ray AJC 2006

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

29 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

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

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

32 Targeting the high risk patient with an unmet need ACS patient DM A low HDL-C Heightened inflammation

33 One target but multiple effects in the right patient

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