ESC Geoffrey Rose Lecture on Population Sciences Cholesterol and risk: past, present and future
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1 ESC Geoffrey Rose Lecture on Population Sciences Cholesterol and risk: past, present and future Rory Collins BHF Professor of Medicine & Epidemiology Clinical Trial Service Unit & Epidemiological Studies Unit University of Oxford
2 Research grants to Oxford University for independent clinical trials and other research from the pharmaceutical industry (including AstraZeneca, Bayer, GSK, Merck, Solvay) CTSU has a policy of not accepting honoraria, consultancies or other payments from industry (except for reimbursement of the costs for travel and accommodation at scientific meetings)
3 CHD incidence and cholesterol in different populations (estimated from Ancel Keys; 1980)
4 Hazard ratio (floating absolute risks & 95% CI) Prospective Studies Collaboration: CHD mortality versus total CHOLESTEROL in each decade of age 33,744 deaths at ages Age at risk 1 mmol/l total cholesterol % risk % risk % risk % risk % risk Usual total cholesterol (mmol/l) Lancet 2007
5 For Debate: Should there be a moratorium on the use of cholesterol lowering drugs? It is difficult to justify the general use of cholesterol lowering drugs when the data available from clinical trials fail to show reductions (and may show increases) in mortality. Davey Smith; BMJ 1992
6 Meta-analysis of (predominately) pre-statin cholesterol-lowering trials in primary prevention (Davey Smith; BMJ 1992) Cause of death Odds ratio (95% CI) CHD 0.72 ( ) Other cardiac 1.59 ( ) Cancer 1.33 ( ) Injury 1.75 ( ) Other 1.69 ( ) All causes 1.16 ( )
7 British news coverage: Guardian (1992)
8 Medical news: Hospital Doctor (1992)
9 Cholesterol Treatment Trialists (CTT) Collaborative meta-analyses (Lancet 2010) Statin versus control 26 trials involving 130,000 patients 1.1 mmol/l difference at 1 year Follow-up for 4.8 years More versus less statin 5 trials involving 40,000 patients 0.5 mmol/l difference at 1 year Follow-up for 5.1 years
10 CTT meta-analysis of STATIN vs CONTROL trials: Effects on MAJOR VASCULAR EVENTS per mmol/l LDL-C reduction No. of events (% pa) Statin Control Relative risk (CI) Nonfatal MI CHD death Major coronary event 2310 (0.9%) 1242 (0.5%) 3380 (1.3%) 3213 (1.2%) 1587 (0.6%) 4539 (1.7%) 0.74 ( ) 0.80 ( ) 0.76 ( ) CABG PTCA Unspecified Coronary revascularisation 816 (0.3%) 601 (0.2%) 1686 (0.6%) 3103 (1.2%) 1126 (0.4%) 775 (0.3%) 2165 (0.8%) 4066 (1.6%) 0.76 ( ) 0.78 ( ) 0.76 ( ) 0.76 ( ) Ischaemic stroke Haemorrhagic stroke Unknown stroke Any stroke 987 (0.4%) 188 (0.1%) 555 (0.2%) 1730 (0.7%) 1225 (0.5%) 163 (0.1%) 629 (0.2%) 2017 (0.8%) 0.80 ( ) 1.10 ( ) 0.88 ( ) 0.85 ( ) Major vascular event 7136 (2.8%) 8934 (3.6%) 0.79 ( ) 99% 95% CI Statin better Control better Lancet 2010
11 CTT meta-analysis of MORE vs LESS trials: Further reductions in MAJOR VASCULAR EVENTS per mmol/l LDL-C reduction subdivided by baseline LDL cholesterol No. of events (% pa) Baseline LDL More statin Less statin Relative risk (CI) < 2 2,< ,<3.0 3,< (4.6) 1189 (4.2) 1065 (4.5) 517 (4.5) 303 (5.7) 795 (5.2) 1317 (4.8) 1203 (5.0) 633 (5.8) 398 (7.8) 0.71 ( ) 0.77 ( ) 0.81 ( ) 0.61 ( ) 0.64 ( ) Total 3837 (4.5) 4416 (5.3) 0.72 ( ) 99% or 95% CI More statin better Less statin better Lancet 2010
12 CTT meta-analysis: Effects on MAJOR VASCULAR EVENTS per mmol/l LDL-C reduction by participant characteristics No. of patients (% pa) Statin/more Control/less Relative risk (CI) per mmol/l LDL-C reduction Previous coronary disease: CHD Non-CHD vascular None 8395 (4.5%) 674 (3.1%) 1904 (1.4%) (5.6%) 802 (3.7%) 2425 (1.8%) 0.79 ( ) 0.81 ( ) 0.75 ( ) Diabetes: Type 1 diabetes Type 2 diabetes No diabetes 145 (4.5%) 2494 (4.2%) 8272 (3.2%) 192 (6.0%) 2920 (5.1%) (4.0%) 0.77 ( ) 0.80 ( ) 0.78 ( ) Sex: Male Female 8712 (3.5%) 2261 (2.5%) (4.4%) 2625 (2.9%) 0.77 ( ) 0.83 ( ) Age (years) 65 >65, 75 > (2.9%) 4032 (3.7%) 885 (4.8%) 7455 (3.6%) 4908 (4.6%) 987 (5.4%) 0.78 ( ) 0.78 ( ) 0.84 ( ) Body mass index (kg/m 2 ): <25 25,< (3.0%) 5033 (3.3%) 2732 (3.3%) 3688 (3.7%) 6125 (4.1%) 3331 (4.1%) 0.79 ( ) 0.78 ( ) 0.78 ( ) Smoking status: Current smokers Non-smokers 2268 (3.6%) 8703 (3.1%) 2896 (4.7%) (3.9%) 0.78 ( ) 0.78 ( ) Total (13.0%) (15.8%) 0.78 ( ) 99% or 95% CI Statin/more better Control/less better Lancet 2010
13 CTT meta-analysis: Effects on MAJOR VASCULAR EVENTS per mmol/l LDL-C reduction by year Statin/ More statin No. of patients Contr ol/ Less statin Relative risk (CI) 0-1 year 1-2 years 2-3 years 3-4 years 4-5 years 5+ years All groups T rend c 2 1 = 14.53; p< (4.1%) 2112 (2.7%) 1763 (2.6%) 1508 (2.6%) 1224 (2.6%) 869 (3.1%) 3952 (4.7%) 2645 (3.3%) 2318 (3.4%) 1954 (3.4%) 1486 (3.2%) 995 (3.7%) (13.0%) (15.8%) 0.88 ( ) 0.77 ( ) 0.73 ( ) 0.72 ( ) 0.77 ( ) 0.76 ( ) 0.78 ( ) 99% or 95% CI Statin/more statin better Control/less statin better Lancet 2010
14 Cochrane Library press release (2011) Statins: Benefits Questionable In Low-Risk Patients.. less evidence that statins are beneficial in those who have no history of CVD, given that the absolute numbers of people who benefit will inevitably be lower, and statins are recognised as having harmful effects in some people..therefore, in people at low risk of heart disease, statins might do more harm than good.
15 CTT meta-analysis: Effects on MAJOR VASCULAR EVENTS per mmol/l LDL-C reduction subdivided by RISK 5-year MVE risk at baseline Events (% per annum) Statin/more Control/less RR (CI) Trend test <5% 167 (0.4) 254 (0.6) 0.62 ( ) 5%,<10% 604 (1.1) 847 (1.6) 0.69 ( ) 10%,<20% 3614 (3.0) 4195 (3.5) 0.79 ( ) 20%,<30% 4108 (4.7) 4919 (5.8) 0.81 ( ) 2 c 1 = 4.29 (p=0.04) 30% 2787 (7.6) 3458 (9.8) 0.79 ( ) Overall (3.3) (4.0) 0.79 ( ) p< % or 95% limits Statin/more better Control/less better Lancet 2012
16 ABSOLUTE BENEFIT: Major Vascular Events avoided per 1,000 treated over 5 years Lancet 2012
17 CTT meta-analysis: Effects on site-specific CANCER INCIDENCE per mmol/l LDL-C reduction No. of first cancers (% pa) Statin/more Control/less Relative risk (CI) per mmol/l LDL-C reduction Gastrointestinal 1166 (0.3%) 1194 (0.3%) 0.97 ( ) Genitourinary Respiratory 1596 (0.5%) 813 (0.2%) 1645 (0.5%) 814 (0.2%) 0.97 ( ) 1.00 ( ) Female breast 267 (0.3%) 241 (0.3%) 1.07 ( ) Haematological 305 (0.1%) 291 (0.1%) 1.04 ( ) Melanoma 159 (0.0%) 142 (0.0%) 1.14 ( ) Other/unknown 754 (0.2%) 737 (0.2%) 1.04 ( ) Any 5060 (1.4%) 5064 (1.4%) 1.00 ( ) 99% or 95% CI Statin/more better Control/less better No emerging cancer excess with prolonged follow-up Lancet 2010
18 Statin-related myopathy/rhabdomyolysis Muscle disorder Definition Frequency (per annum) Myopathy Creatine kinase (CK) >10x ULN with muscle symptoms <1/10,000 Rhabdomyolysis Myopathy with CK >40x ULN and evidence of renal dysfunction ~1/100,000 Risk influenced by dose (e.g. 10-fold increase with 40 vs 80 mg simvastatin), certain drugs and other factors (e.g. ethnicity)
19 Meta-analysis of statin trials: Diagnosis of diabetes (Sattar; Lancet 2010)
20 Percentage suffering event HPS: In-trial and post-trial effects on MVE risk of 5-year allocation to simvastatin vs placebo PLACEBO (originally) SIMVASTATIN (originally) Years of follow-up Lancet 2011
21 MHRA Public Assessment Report Statins: updates to product safety information November 2009 Based on the evidence in the review, it was decided that the following adverse events were a class effect of statins as a whole: sleep disturbances; memory loss; sexual disturbance; depression; interstitial pneumonopathy.
22 FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs (February 2012) Memory loss and confusion have been reported with statin use. These reported events were generally not serious and went away once the drug was no longer being taken.
23 MHRA review of the effects of statins on memory loss A total of 333 cases of memory loss were reported post-marketing a causal relationship between simvastatin and memory loss cannot be ruled out. In the WOSCOPS, CARE and PROSPER clinical studies the incidence of memory loss was similar in pravastatin-treated and placebo-treated patients.
24 HPS: Cognitive impairment (TICS-m <22/39) at final follow-up visit (Lancet 2002) Age (years) at randomisation Simvastatin (8086) Placebo (7834) < % 17.8% 65< % 25.4% % 36.2% ALL PATIENTS 23.7% 24.2% Comparing treatment groups: P-value = 0.4
25 PROSPER: Effects of pravastatin on cognitive function in 5804 randomised participants aged years (Trompet et al; J Neurol 2010)
26 Non-randomised population study: Estimated effects of 5 years of statin therapy in men aged with 10 year CV risk 20% (Hippisley-Cox; BMJ 2010) Outcome HR (95% CI) NNT/NNH (95% CI) CV events 0.76 (0.67 to 0.86) -33 (-57 to -24) Cataract 1.32 (1.26 to 1.37) 52 (44 to 63) Myopathy 6.15 (5.19 to 7.30) 91 (74 to 112) Liver dysfunction 1.53 (1.42 to 1.66) 142 (115 to 180) Acute renal failure 1.61 (1.39 to 1.87) 346 (245 to 539) Based on average of only 2.5 years of statin exposure and partial adjustment for potential confounders
27 HPS randomised placebo-controlled trial of 40 mg simvastatin daily for 5 years: Effect on CATARACT Simvastatin (10,269) Placebo (10,267) Cataract report or extraction 393 (3.8%) 404 (3.9%) Risk ratio (95% CI): 0.96 ( ) Not consistent with the excess observed in the non-randomised population study
28 Requirements for evidence to support claims related to safety versus efficacy of treatments Treatment not known to be effective Lower threshold for safety concerns (compared with evidence for efficacy) Treatment known to be effective (e.g. statins) Higher threshold for safety concerns (of similar strength to evidence that is typically required for efficacy)
29 Balance of benefits and risks of statin therapy in LOWEST RISK groups (<10% over 5 years) 5 year effects per mmol/l LDL-C reduction per 1000 individuals treated with a statin: 11 fewer major vascular events* VERSUS 0.5 more myopathy cases (0.1 rhabdomyolysis) 5 new diagnoses of diabetes mellitus (which may translate into 0.2 fewer MVEs avoided) * includes 0.5 extra haemorrhagic strokes
30 Five year risk of a major vascular event, % Absolute effects on MAJOR VASCULAR EVENTS of lowering LDL cholesterol with STATIN therapy More statin Statin Control Or: Combined evidence: ~40% 34% relative risk reduction with mmol/l reduction (since 0.78 x 0.85 = 0.66) 22% relative risk reduction with 1.0 mmol/l reduction 15% relative risk reduction with 0.5 mmol/l more reduction LDL cholesterol (mmol/l)
31 Ezetimibe added to statin: Equivalent to 3 doublings of the statin dose (minimizing excess of myopathy) Statin 10 mg 20 mg 40 mg 80 mg Statin 10 mg + Ezetimibe 10 mg % reduction in LDL cholesterol
32 Proportional reduction in atherosclerotic event rate (95% CI) SHARP trial: Effect on major vascular events of ezetimibe 10 mg plus simvastatin 20 mg daily 30% Statin vs control (21 trials) 25% 20% 15% 10% 5% More vs Less (5 trials) SHARP 17% risk reduction 0% Mean LDL cholesterol difference between treatment groups (mmol/l) Lancet 2011
33 IMPROVE-IT: Effects on cardiovascular events of further LDL-C reduction with EZETIMIBE (Califf AHJ 2010; Cannon AHJ 2008) 18,142 patients stabilised after acute coronary syndrome Random allocation: Ezetimibe 10 mg daily versus placebo (added to simvastatin mg daily for LDL-C <80 mg/dl) Predicted LDL-reduction: 0.39 mmol/l (15 mg/dl) Primary outcome: CV death, MI, hospitalisation for angina, revascularisation or stroke Predicted risk reduction: 9.4% Statistical power: 5250 events (by 2014) during minimum follow-up of 2.5 years yields >90% power at 2P=0.05
34 CETP inhibitors: Effects on blood lipids Torcetrapib Dalcetrapib Evacetrapib Anacetrapib 60 mg daily 600 mg daily 100 mg daily 100 mg daily Total cholesterol +4% +8% n/a +16% LDL-cholesterol -25% -2% -20% -40% Triglycerides -10% -3% -5% -8% Apolipoprotein B -12% +4% n/a -20% HDL-cholesterol +60% +30% +75% +140% Apolipoprotein A1 +25% +10% n/a +45%
35 ILLUMINATE: Effects of torcetrapib on cardiovascular events (NEJM 2007) 15,067 patients with history of CVD or type 2 diabetes Randomised: Torcetrapib 60mg daily versus placebo (added to atorvastatin) Observed lipid difference: LDL-C: 0.58 mmol/l (22.4 mg/dl) lower HDL-C: 0.87 mmol/l (33.7 mg/dl) higher Primary endpoint: CHD death, MI, unstable angina or stroke Predicted risk reduction: 21% Target: 1820 events followed for mean of 4.5 years. Terminated early with median follow-up of 550 days due to an increased risk of death and cardiovascular events (associated with increased BP and other off-target effects)
36 RADIANCE 1: Effects of torcetrapib on mean maximum carotid IMT in patients with heterozygous FH (Kastelein; Lancet 2007)
37 Dal-OUTCOMES: Effects of dalcetrapib on cardiovascular events 15,000 acute coronary syndrome patients Randomised: Dalcetrapib 600mg daily versus placebo (added to standard LDL-lowering therapy) Predicted lipid difference: LDL-C: No effect HDL-C: 0.28 mmol/l (11 mg/dl) higher Primary endpoint: CHD death, MI, ACS hospitalisation, cardiac arrest or atherothrombotic stroke Predicted risk reduction: 15% Target: 1600 events followed for at least 2 years. Terminated early in 2012 due to a lack of clinically meaningful efficacy.. No safety signals.
38 ERFC: Associations of triglycerides, HDL-C and LDL-C with CHD before and after adjustment (300,000 participants in 68 prospective studies) Hazard ratio and 95% CI 3.5 Triglycerides 3.5 HDL-C 3.5 Non-HDL-C Usual triglyceride (mg/dl) Usual HDL-C (mg/dl) Usual non-hdl-c (mg/dl) Adjusted for age and sex only Further adjusted for several risk factors JAMA 2009
39 HPS3-REVEAL: Assessment of effects on anacetrapib on cardiovascular events 30,000 patients with atherosclerotic vascular disease Randomised: Anacetrapib 100 mg daily versus placebo (added to atorvastatin mg daily) Predicted lipid differences: LDL-C: 0.5 mmol/l (19 mg/dl) lower HDL-C: 1.0 mmol/l (38 mg/dl) higher Primary outcome: Major Coronary Event (i.e. coronary death, non-fatal MI or coronary revascularization) Predicted risk reduction: 15% (or more) Statistical power: >1900 events during median followup of 4 years (mid-2016) yields 90% power at 2P=0.01
40 PCSK9 nonsense mutations: Life-long effects on lipids, carotid IMT and CVD (Cohen; NEJM 2006) Non-carriers (3278) Carriers (85) LDL-C 3.6 mmol/l 2.6 mmol/l HDL-C 1.4 mmol/l 1.4 mmol/l Hazard ratio (& 95% CI) CIMT 0.73± ±0.13 P=0.04 CHD 319 (9.7%) 1 (1.2%) 0.11 ( ) P=0.03 Stroke 217 (6.6%) 6 (7.1%) 1.07 ( ) P=0.87
41 Meta-analysis of effects of PCSK9 R46L genotype on LDL-C and CHD risk (Benn; JACC 2010) 1639 carriers of 46L in 7 population studies 0.39 ( ) mmol/l lower LDL-C per allele; with consistent results in different studies 8,830 CHD cases and 36,869 controls CHD hazard ratio of 0.72 (95% CI ); but with significant variability between studies
42 Effects on LDL-C of adding 2- or 4-weekly subcutaneous PCSK9 antibody to atorvastatin (McKenney; JACC 2012)
43 Conclusions for lipid-modifying therapy Each 1 mmol/l LDL-C reduction reduces the annual rate of major vascular events by about one-fifth Larger LDL-C reductions safely produce definite larger reductions in the incidence of heart attacks, revascularisations and ischaemic strokes Similar proportional reductions in all of the subgroups studied (including renal disease and 1 prevention) No threshold within the cholesterol range studied, which implies that reducing LDL-C by 2-3 mmol/l would reduce vascular event risk by about 40-50% Benefits of raising HDL-C remain to be demonstrated
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