From Population Studies to Clinical Trials

Transcription

1 From Population Studies to Clinical Trials Prof Kausik Ray MBChB, MD, MPhil (Cantab), FRCP (Lon), FRCP (Ed), FESC, FACC, FAHA Department of Primary Care and Public Health School of Public Health, Imperial College London, London, UK

2 Do statins increase the risk of diabetes?

3 Yes Sattar N, Ray. Lancet 2010; 375:

4 Is the risk a class effect?

5 Yes Sattar N, Ray. Lancet 2010; 375:

6 Is there a dose effect?

7 Yes Preiss...Ray. JAMA 2011;305:

8 Is there a difference between statins at high doses?

9 No Preiss...Ray. JAMA 2011;305:

10 Impact

11 Who is more likely to develop Diabetes?

12 Risk greater at increasing age Sattar...et al Ray Lancet feb17th

13 What s the mechanism?

14 We used SNPs in the HMGCR gene (rs and rs12916) as proxies for HMGCR statin inhibition. In up to 223,463 individuals (43 studies), we examined associations of these variants with plasma lipid, glucose and insulin concentrations, weight, and prevalent and incidentt2d The findings were compared with a meta-analysis of newonset T2D and weight change data from up to 20 major randomised statin cardiovascular end-point trials (n=129,170) Swerdlow et al Ray KK Lancet 2014

15 Randomisation to test causality Drug intervention Genetics RCT Sample Mendelian randomisation Population Randomisation Random allocation of alleles Intervention Control Genotype aa Genotype AA Biomarker lower Biomarker higher Biomarker lower Biomarker higher CV event rate lower CV event rate higher CV event rate lower CV event rate higher Hingorani et al, Lancet 2005

16 Associations of HMGCR rs with major plasma lipid fractions Swerdlow et al Ray KK Lancet 2014

17 Associations of HMGCR rs with plasma glucose and plasma insulin Swerdlow et al Ray KK Lancet 2014

18 Association of HMGCR rs with risk of T2D Swerdlow et al Ray KK Lancet 2014

19 Associations of HMGCR rs with BMI and body weight Swerdlow et al Ray KK Lancet 2014

20 Associations of HMGCR rs with waist circumference, hip circumference and waist:hip ratio Swerdlow et al Ray KK Lancet 2014

21 Effect of statin therapy on body weight (kg) in 15 trials (random effects meta-analysis) Swerdlow et al 2014

22 Are all statins the same?

23 Cumulative Incidence Rate Primary Outcome: Cumulative Incidence of Diabetes HR 0.82 (95% CI: ) p=0.041 (Stratified log-rank test) Control 0.50 Pitavastatin 0.25 No. at Risk Control 556 Pitavastatin Median follow up 2.8 years (range 2-6 years) Average pitavastatin dose 1.3mg Months since randomisation rd ADA 2013, Chicago, IL, USA: Late Breaking Studies

24 Change in blood glucose from baseline to end of followup in non-diabetic subjects STUDY VISION TRUTH COMPACT-CAD NK-104-Taiwan PEACE NK NK NK INTREPID PREVAIL NK NK CH NK NK NK I-V Overall (I-squared = 1.7%, p = 0.432) D+L Overall Intervention reduces blood glucose Intervention increases blood glucose Vallejo-Vaz AV et al Ray KK Atherosclerosis 2015

25 Vallejo-Vaz AV et al Ray KK Atherosclerosis 2015

26 Vallejo-Vaz AV et al Ray KK Atherosclerosis 2015

27 Vallejo-Vaz AV et al Ray KK Atherosclerosis 2015

28 Impact? Data submission to the FDA to consider a different label for pitavastatin

29 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 ( ) 64 (54 71) Coronary death ( ) 41 (24 54) Non-fatal myocardial infarction ( ) 37 (19 51) Cerebrovascular disease ( ) 42 (25 55) Ischaemic stroke ( ) 1 (0 20) Haemorrhagic stroke ( ) 0 (0 26) Unclassified stroke ( ) 33 (12 48) Other vascular deaths ( ) 0 (0 26) Hazard ratio (diabetes vs. no diabetes) SBP, systolic blood pressure; BMI, body mass index; HR, hazard ratio; CI, confidence interval; I 2, heterogeneity measure Seshasai SR et al Ray KK. on behalf of Emerging Risk Factors Collaboration. Lancet 2010;375:

30 Estimated life years lost among those with diabetes Seshasai SR et al. on behalf of Emerging Risk Factors Collaboration. New Engl J Med 2011;364:

31 Effect of 0.9% lowering of HbA1c on CVD outcomes in 33,042 patients across five studies Outcome OR (95% CI) I 2 Non-fatal MI 0.83 (0.75, 0.93 ) 0% CHD 0.85 (0.77, 0.93) 0% Stroke 0.93 (0.81, 1.06) 0% All-cause mortality 1.02 (0.87, 1.19) 58% Odds ratio Intensive therapy better Standard therapy better MI, myocardial infarction; OR, odds ratio Ray KK, Seshasai SR et al. Lancet 2009;373:

32 Coronary heart disease Benefit of different interventions per 200 diabetic patients treated for 5 years Per 4mmHg lower SBP Per 1mmol/L lower LDL-C Per 0.9% lower HbA1c LDL-C, low density lipoprotein cholesterol Ray KK, Seshasai SR et al. Lancet 2009;373:

33 ICCP Research Areas CVD Risk assessment CVD Risk Management Evidence synthesis Randomised controlled trials Discovery of novel risk factors Establishment of multi-national registries to identify and tackle gaps Meta-analyses of observational studies and RCTs Design and conduct of phase III RCTs Validation of existing risk factors Development of novel risk prediction algorithms Establishment of large-scale cohort studies using innovative approaches Policy development on CVD prevention 1 and 2 prevention

34 Observational studies underway EAS FHSC >55 countries formally involved (leading) TOGETHER burden of cardio-metabolic risk factors in 250,000 (leading) FUNDED ADORE diabetes diagnosis, management and consequences in Asian Pacific (partners) TIGRIS DAPT in 2 prevention (partners, global registry)

35 Studies underway HEART 360 Validation of a software tool to improve patient drug/lifestyle compliance with AHA Statin benefit in FH in WOSCOPS FUNDED Impact of microvascular disease on CVD outcomes in diabetes using CPRD

36 Prof Ray RCT Trial Involvement at SC/EC level DECLARE - Evaluating a SGLT2 inhibitor in diabetes CAMELLIA - Evaluating a novel weight loss drug Odyssey Outcomes - PCSK9 inhibitor and CVD events THEMIS - DAPT in diabetes and stable CHD STRENGTH - Epanova (fish oil) addition to standard therapy in people with high CVD risk, high TG and low HDL BETonMACE - BET inhibition in patients with diabetes and ACS

37 Prof Ray RCT Trial Involvement at SC/EC level CARAT - IVUS study of the effect of CER 001 infusion on atherosclerosis ACCENTUATE - Effect of CETP inhibition with EVACETRAPIB on lipid goal attainment CVD outcomes study with TA-8995 ORION- A novel mechanism of PCSK9 inhibition and lipid outcomes (phase 2)

38 FH

39 Familial Hypercholesterolaemia Estimated millions of individuals worldwide with FH by WHO regions and by income groups Nordestgaard BG et al. Eur Heart J 2013;34:

40 Familial Hypercholesterolaemia Estimated % of individuals diagnosed with FH in different countries/ territories, as a fraction of those theoretically predicted based on a frequency of 1/500 in the general population Nordestgaard BG et al. Eur Heart J 2013;34:

41 Cumulative LDL-C burden with and without familial hypercholesterolaemia as a function of age of initiation of statin therapy CHD, coronary heart disease; CV, cardiovascular; FH, familial hypercholesterolaemia; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. Nordestgaard BG, et al. Eur Heart J 2013;34:

42 Despite available treatment approaches, a significant percentage of familial hypercholesterolaemia patients are not at goal 100 n= Attainment of LDL-C 60 target (%) Only 21% of HeFH patients achieved the LDL-C treatment goal of <2.5 mmol/l Of those not at target, 73% did not use maximum statin treatment or combination with ezetimibe LDL-C target (mmol/l) Cross-sectional study was conducted in outpatient lipid clinics of three academic centres and two regional hospitals. Patient records of known HeFH patients were retrieved and data were reviewed on the use of lipid-lowering medication, plasma lipids and lipoproteins, safety laboratory results, and reasons for not achieving treatment goals. HeFH, heterozygous familial hypercholesterolaemia; LDL-C, low-density lipoprotein cholesterol. Pijlman AH, et al. Atherosclerosis 2010;209:

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44 Coordinating Centre EAS FHSC Steering Committee Coordinating Centre School of Public Health, ICL National Lead investigators Central point for data collation, cleaning, queries and sharing Dr. Antonio J. Vallejo-Vaz Lead Scientist Dr. Sreenivasa R. Kondapally Seshasai Mrs. Della Cole Individual Sites

45 EAS FHSC NLIs from: 39 countries + 5 additional countries in partnership with the 10 Countries Studies + 11 additional countries in partnership with the ScreenPro FH programme = total 55 countries. Others, potentially: - Iceland - Central Africa regions - Tunisia - Ireland - Switzerland - USA

46 EAS/ESC Guidelines

47 2013 ACC/AHA Guideline

48 WOSCOPS Within 6 months 4S Within 1 year Trial evidence Trial evidence

49 LDL receptor function and life cycle For illustration purposes only 49

50 The role of PCSK9 in the regulation of LDL receptor expression For illustration purposes only 50

51 Impact of a PCSK9 mab on LDL receptor expression For illustration purposes only mab 51

52 PCSK9 Therapeutic Hypothesis LDLR LDL Endosome Lysosomal degradation Anti-PCSK9 Mabs Transiently block PCSK9 binding To LDL receptor (LDLR) LDLR synthesis PCSK9 Synthesis Inhibitors Durably block PCSK9 synthesis and all intracellular and extracellular PCSK9 functions ALN-PCS PCSK9 synthesis PCSK9 mrna Nucleus PCSK9 52

53 Mean (SEM) % PCSK9 Knockdown (Change from Baseline) Initial ALN-PCSsc Phase 1 Study Results SAD PCSK9 Knockdown Relative to Baseline Treatment Placebo 25 mg 100 mg 300 mg 500 mg 800 mg Months Day/Treatment combinations where N=1 not displayed 53 Data in database as of 04 August 2015

54 Who Should Get These New Treatments Statin Side Effects/ Intolerance High Absolute CVD Risk 54

55 Statin Intolerance Funded- 93k Retrospective Study of Statin Discontinuation, Reasons, Consequences. Second grant outline submitted Ailsa Mackay, Michael Soljak, Roger Newson, Azeem Majeed PROSPECTIVE Observational Study of 1000 GP practices in UK to study in more detail the reasons and rates of statin discontinuationprotocol being finalised 55

56 Absolute Risk Score for People Receiving Statins 56

57 57 Bhatt JAMA REACH REGISTRY

58 58 Bhatt JAMA REACH REGISTRYc

59 5-year CVD rate Net Benefit from Further Reduction in Relative Risk of CVD events no harm) 5-year NNT 10-year NNT LDL-C reduction (mg/dl) 10-year LDL-C reduction (mg/dl) CVD Relative risk reduction rate Relative risk reduction 10% 15% 20% 25% 35% 50% 10% 15% 20% 25% 35% 50% 25% % % % % % % % % % IMPROVE-IT LDL-C 70 vs 54 mg/dl (Consistent with ezetimibe average 20% LDL-C) Chronic CHD* on statin LDL-C mg/dl Chronic CHD* on statin LDL-C mg/dl ( 25 mg/dl/~15% RRR) LDL-C 61 mg/dl /~35% RRR: (add Ezetimibe) OR mg/dl with 60% LDL-C OR add PCSK-mAb? *5-year hard CVD rate TNT chronic CHD atorvastatin10 mg10.9%/atorvastatin % (LaRosa J, et al. NEJM 2005; 352: ); CVD: Cardiovascular disease; NNT: Number-needed-to-treat; IMPROVE-IT ACS+1 high RF (Simvastatin 16% hard CVD 5-y) Cannon C, et al. AHA Scientific Sessions 2014, Chicago IL); 59 Robinson and Ray in Review

60 60 Robinson and Ray in Review

61 Absolute Risk Score for People Receiving Statins Expression of interest for a grant 61

62 ICCP Team Professor Kausik Ray (Lead) Dr Sreenivasa Rao Kondapally Seshasai (Honorary Clinical Lecturer) Dr Antonio J. Vallejo-Vaz (Clinical Research Fellow) Dr Allyah Abbas (NIHR Academic Clinical Fellow) Dr Osman Najam (NIHR Academic Clinical Fellow) Mrs Della Cole (Collaborator and Senior Cardiac Nurse Specialist) Prof Kess Hovingh (Collaborator from AMC, Visiting Prof) Dr Handrean Soran (Collaborator from Univ of Manchester, Visiting SL)

63 Other ICCP Projects Imaging markers of atherosclerosis with cardiometabolic traits University of São Paulo Lipid lowering in FH (4S) Novel hypotheses in clinical trial databases (CATS) Prevalence of FH and risk factor control in 1 care CPRD database Lipid/BP treatment meta analysis consortium Level of lipid risk factor control and outcomes in the THIN database Effect of statins on plasminogen activator inhibitor-1 MultiGAP programme LDL-C goals attainment, therapy and risk factors in high risk patients in Hungary Effect of saxagliptin on blood pressure, heart rate, BMI and other factors sub-analysis from the SAVOR-TIMI 53 study