Management of LDL as a Risk Factor. Raul D. Santos MD, PhD Heart Institute-InCor University of Sao Paulo Brazil

Transcription

1 Management of LDL as a Risk Factor Raul D. Santos MD, PhD Heart Institute-InCor University of Sao Paulo Brazil

2 Disclosure Consulting for: Merck, Astra Zeneca, ISIS- Genzyme, Novo-Nordisk, BMS, Pfizer, Lilly, Amgem, Aegerion, Sanofi Sponsored research: ISIS-Genzyme, GSK, and Roche Speakers Bureau: Pfizer, Merck, Astra Zeneca, Abbott, Biolab and Novartis

3 Management of LDL as a Risk Factor Epidemiological association of cholesterol and CVD Evidence for cholesterol lowering Safety and cost effectiveness Statins and diabetes onset Unmet needs The future

4 LDL particles Source: The Lancet 2010; 375: (DOI: /S (10) )

5 What is the importance of cholesterol for CVD?

6 Blood cholesterol and vascular mortality by age, sex and blood pressure: a meta-analysis of individual data from 61 prospective studies with vascular deaths Lancet 2007; 370:

7 N=900,000 Lancet 2007; 370:

8 What is non-hdl cholesterol? Triglycerides Cholesterol All lipoproteins HDL LDL IDL VLDL CM remnants apoa-i apob apob apob apob 48 non-hdl Courtesy Roger Blumenthal non HDL-C = Total Cholesterol HDL-C

9 Non-HDL-cholesterol, CHD and, Ischemic Stroke N=302,430 4X more potent for CHD vs. Stroke N=173,312 CHD Ischemic Stroke FUP 2.79 million /persons years JAMA 2009;302:

10 Intervention studies with statins What s the evidence?

11 Lancet 2010.; 376:

12 Impact of 40 mg/dl reduction on LDL-C upon major cardiovascular events and mortality CTT 2010 Relative Risk (95% CI) All cause mortality CHD mortality Other cardiac deaths Stroke deaths Major vascular events Non-fatal MI Myocardial revascularization Ischemic stroke Cancer incidence Hemorrhagic stroke 0.90 ( ), p<0.0001** 0.80 ( ); p<0.0001** 0.89 ( ); p=0.002** 0.96 ( ); p= ( ); p< ( ); p< ( ); p< ( ); p< ( ); p= ( ); p=0.2 Adapted from The Lancet 2010.; 376: **- CI 99%

13 Reduction in CHD Events % Risk Reduction (%) in CHD Events p/ 39 mg/dl LDL-C Lowering According to Treatment Length 1 st year 2 nd year 3 rd to 5 th years >6 th year Adapted from Law MR et al BMJ 2003;326:1423

14 + Importance of reducing non-hdl-c 1% non-hdl-c = 1% CHD risk Evaluated studies 14 with statins (n=100,827) 7 with fibrates (n=21.647) 6 with niacin (n=4.445) 1 with resins (n=3.806) 1 with diet (n=458) 1 with ileal bypass (n=838) TOTAL 132,021 patient AVERAGE FOLLOW-UP 4.5 Y J Am Coll Cardiol 2009;53:

15 The ideal cholesterol level? Is really lower the better?

16 LDL-C of MI Subjects in The USA: Primary Prevention LDL N=48,093 >130 mg/dl 27.9% mg/dl 30.6% < 100 mg/dl 41.5% <70 mg/dl = 12.5% Sachedeva A et al. Am Heart J 2009;157:111-7

17 Relative risk of CHD death Low Cholesterol A China Business? 2.0 MRFIT Shanghai Chen et al. BMJ. 1991;303: Kannel et al. Am Heart J : Total Plasma Cholesterol (mg/dl) 272

18 Proportional reduction in atherosclerotic event rate (95% CI) CTT: Effects on Major Atherosclerotic Events 30% Statin vs control (21 trials) 25% 20% 15% More vs Less (5 trials) 10% 5% 0% Mean LDL cholesterol difference between treatment groups (mg/dl) Lancet 2010.; 376:

19 What is the cost effectiveness of LDL-C lowering? Who will benefit the most?

20 Baseline LDL-C and risk reduction Lancet 2010.; 376:

21 Cardiovascular events per 40 mg/dl reduction in LDL-C in 5 years: CTT Mean LDL-C 148 ( ) mg/dl Relative risk reduction Primary Prevention 20% 20% Secondary Prevention Absolute risk reduction Events avoided per 1,000 (CI 95%) 2% 5% 25 (19-31) 48 (39-57) NNT Adapted from CTT Lancet 2005;366:

22 Does cholesterol lowering cause cancer?

23 Alsheikh-Ali et al. JACC 2008;52:1141-7

24 LDL-C Reduction and Cancer Incidence Lancet 2010.; 376:

25 Do Statins Increase the Risk of Type 2 Diabetes?

26 Statins and The Risk of Diabetes: Meta-analysis Relative increment 9% NNH= 255 Source: The Lancet 2010; 375: (DOI: /S (09) )

27 Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-Dose to Moderate-Dose Statin Therapy Preiss, D. et al. JAMA 2011;305: NNH=498/ year NNT= 155/year

28 Risk of new-onset T2DM: baseline fasting glucose > 100 mg/dl, fasting triglycerides>150 mg/dl, BMI >30 kg/m2, and a history of hypertension Waters DD et al. JACC 2011; 57:

29 Do Statins Increase The Risk of Hemorhagic Stroke?

30 N=248,391 Randomized Trials Observational Studies Hackman et al. Circulation Nov e-pub

31 Do Statins Cause Cognitive Changes?

32 FDA: Statins can cause cognitive changes that are generally reversible 333 cases in post-marketing surveys HPS- memory loss objectively measured by TICS questionnaire 23.4% vs % simvastatin vs. placebo p=0.4 Dementia 0.3% vs. 0.3% Other phsyquiatric changes 0.7% vs. 0.7% Lancet 2002;360: 7 22

33 Statins and severe muscle damage

34 Severe muscle disease with statins: CTT N=170,000 in 26 trials Defined ad CK levels > 10 x ULN Simvastatin 80 mg vs mg 4/10,000 vs 1/10,000 Not seen with high dose atorvastatin Not associated with LDL-C lowering Lancet 2010.; 376:

35 What are the unmet needs?

36 % Rates of CHD Patients Attaining LDL-C <70 mg/dl according to gender:ltap-2 n=2993 Gender Total 879/2993 Women 242/ / /940 Success Faillure Men 637/ /2053 P= Santos RD et al. Am Heart J 2009;158:860-6

37 % Non-HDL-C Success Rate by Risk Group Risk Groups 6224/ / / /5930 P<0.001 among risk groups. Risk group and success determined according to NCEP ATP III guidelines. Santos RD et al. Atherosclerosis 2012; 224:150-3

38 What is the future? Present in some cases

39 Antisense oligonucleotides: mechanism of action DNA Transcription mrna Translation Traditional drug Disease-associated protein produced Transcription No translation Antisense drug (oligonucleotide) No disease-associated protein produced Adapted from: Crooke ST, ed. Antisense drug technology: principles, strategies and applications. 2nd ed. Boca Raton, FL: CRC Press, 2007:601

40 Raal FJ, Santos RD et al. Lancet. 2010;375:

41 Lomitapide: Mode of Action Diet Source triglyceride cholesterol Intestinal Cell MT P Chylomicron n Liver Source triglyceride cholesterol Apo B-48 Liver Cell MTP Decreases Secretion into Bloodstream Apo B-100 VLDL 41

42 Mean % Change in LDL-C from BL (95% CI) Lomitapide Efficacy in Phase 3 (Completer Population, N=23) Efficacy Phase Safety Phase 50% Reduction 44% Reduction p<0.001 p<0.001 Mean Dose: 45 mg Mean Dose: 40 mg Study Week LDL-C 352 ± ± 96 (mg/dl): Baseline Week 26 Adapted from Cuchel M et al. Lancet 2013; 381: ± 123 Week 56

43 Impact of an PCSK9 mab on LDL Receptor Expression For illustration purposes only

44 LAPLACE-TIMI 57: Mean Change in LDL-C from Baseline While Receiving Statin Therapy to Week 12 With AMG 145 Intervention Baseline LDL-C (mg/dl) % Change LDL-C Attained LDL-C (mg/dl) Placebo 124 AMG mg Q2W %* 73 AMG mg Q2W %* 54 AMG mg Q2W %* 45 AMG mg Q4W %* 69 AMG mg Q4W %* 60 AMG mg Q4W %* 58 n = 631 * p < for % change in LDL-C vs placebo Giugliano et al. Lancet 2012; 380:

45 % Change from Baseline to Week 12 Changes in Apo B, nonhdl-c, and Lp(a) from Baseline to Week 12 with Alirocumab 10 Apo B nonhdl-c Lp(a) % -2% -0% -13% %* -34%* -26%* -29%* LS mean (SE) 2 median (Q1-Q3) * p < p = %* -56%* -56%* -63%* McKenney et al. J Am Coll Cardiol 2012;

46 Conclusions 1 There is a clear association between cholesterol levels and the risk of CHD death Cholesterol lowering reduces the risk of cardiovascular events and mortality The absolute benefit depends on the risk Cholesterol reduction does not increase the risk of cancer, hemorrhagic stroke or cognitive dysfunction

47 Conclusions 2 Statin use is associated with an increase in the risk of type 2 diabetes Absolute risk is small Greater in those at higher risk of becoming diabetics at baseline There is plenty of room for improvement in prevention of subjects at high risk of CVD