Lipidsenkende behandling:
Nåtid og fremtid
Terje R. Pedersen Oslo Universitssykehus
Seksjon for preventiv kardiologi
Statin behandling
• Sannsynligvis den best dokumenterte
behandling innen kardiovaskulær medisin
• 28+ store randomiserte kontrollerte studier
• 100-vis mindre randomiserte studier
Siste stor-skala randomiserte studie: HOPE-3
Yusuf S, et al. NEJM 2016;374:2021-2031
Rosuvastatin 10 mg Placebo
N=6361 N=6344
Primary prevention patients Intermediate CHD risk
21 Countries including Asia
↓26.5%
3.4 mmol/L
HOPE-3 Risk Factors
• Elevated waist-hip ratio: Female:≥ 0.85, Male ≥0.90
• Low-level HDL-C: Female < 1.3, Male <1.0 mmol/L
• Smoker
• Dysglycemia (no drug treatment)
• Impaired renal function (eGFR < 60 or microalbuminurea)
• Family history of early CHD (Female < 65 Yrs. Male < 55 yrs)
Yusuf S, et al. NEJM 2016;374:2021-2031
CHD
Death + Non-fatal MI, Stroke Heart Arrest, Heart Failure & Revasc.Year
Yusuf S, et al. NEJM 2016;374:2021-31
HOPE-3
HOPE-3: Stroke
Yusuf S, et al. NEJM 2016;374:2021-31
Are very low LDL-C levels safe?
IMPROVE-IT results
Giugliano R, et al. JAMA Cardiol 2017;2:547-555
IMPROVE-IT: Median LDL-C
Giugliano R, et al. JAMA Cardiol 2017;2:547-555
IMPROVE-IT: Adverse events (%) by LDL-C level
Safety
End-point
< 0.8 mmol/L N=941
0.8 – 1.3 mmol/L N=4780
1. 31 – 1.84 mmol/L
N=5504
≥ 1.85 mmol/L N=4026
P-
value for trend
Discontinued
because of AE 9.5 9.4 8.5 8.8 .21
Rhabdo or
myopathy 0 0.3 0.2 0.6 .81
Neurocogn. AE 2.1 2.3 2.9 2.3 .95
Hemorrhagic
stroke 0.3 0.9 0.4 0.6 .50
Non-CVD death 5.8 5.1 5.6 4.9 .50
Cancer 9.0 8.6 8.7 7.5 .04
Giugliano R, et al. JAMA Cardiol 2017;2:547-555
Viktigste problem med statiner:
Muskelsmerter
Systematic Review: Reported Muscle Problems in Placebo-Controlled Statin Trials
Variables Statin Placebo P-value
Any Muscle Problem 7544/59 237 (12.7%) 6735/54 458 (12.4%) 0.06 CK> 3 X ULN 63/13 734 (0.5%) 42/13 740 (0.3%) 0.04 CK> 5 X ULN 13/4 582 ( 0.3%) 6/4 593 (0.13%) 0.11 CK> 10 X ULN 77/39 893 (0.2%) 55/34 499 (0.16%) 0.28 Rhabdomyolysis 15/49 691 (0.03%) 12/52 301 (0.02%) 0.48 Stopped Rx Because
of Muscle Symptoms
109/22 099 (0.49 %) 104/22 019 (0.47%) 0.75
Ganga HV, et al. Am Heart J 2014;168:6-15
22 Placebo-controlled Statin Trials:
Discontinuation Rates
Riaz H, et al. Am J Cardiol 2017;120:774
Statin Trials: Rates of Myopathy
Riaz H, et al. Am J Cardiol 2017;120:774
Internasjonalt: kampanjer mot statiner på
Internett
Kampanje mot statiner på Internet
• Google Search:
– «Statin benefits» : 655 000 results – «Statin risks» : 3 530 000 results
Steven E Nissen: Annals of Internal Medicine 2017;167:281-282 25. July
Facebook mining in the USA 1st month of 2017
• Statins mentioned by 27 500 Facebook users
• 1200 users mentioned side effects of statins
• ~40 million users of statins in the USA
Huesch MD. Drug Safety 2017: DOI 10.1007/s40264-017-0577-3
ASCOT-Lipid-Lowering Arm:
Muscle-related AE in blinded and non-blinded phase Muscle
related AE
Blinded randomized phase
Non-blinded phase
Placebo N=5079
Atorvastatin N=5101
Atorvastatin non-user N=3490
Atorvastatin user
N=6409
Patients (n) 283 298 124 161
AE annual rate
2.00 % 2.03 % 1.00% 1.26%
HR
(95% CI)
1 1.03
(0.88-1.21)
1 1.41
(1.10-1.79)
p-value 0.72 0.006
Gupta A, et al. Lancet 2017;389:2473-2481
Statin trials in children with FH
PLUTO study: 177 pubertal children, placebo or 5, 10 or 20 mg rosuvastatin for 12 + 40 weeks
Pravastatin carotid IMT trial: 214 children 8-18 yrs, placebo or 20 or 40 mg pravastatin, for 2 years
No participant withdrew from the studies because of myalgia
JUPITER: Incidenc of diabetes
Ridker PM, et al. Lancet 2012;380:565-571
JUPITER: Incidence of CVD and of diabetes
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Trial Design
Evolocumab SC
140 mg Q2W or 420 mg QM
Placebo SC
Q2W or QM LDL-C ≥70 mg/dL or
non-HDL-C ≥100 mg/dL
Follow-up Q 12 weeks
Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) 27,564 high-risk, stable patients with established CV disease
(prior MI, prior stroke, or symptomatic PAD)
RANDOMIZED DOUBLE BLIND
Sabatine MS et al. Am Heart J 2016;173:94-101
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
LDL Cholesterol
0 10 20 30 40 50 60 70 80 90 100
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
LDL Cholesterol (mg/dl)
Weeks
Evolocumab
(median 30 mg/dl, IQR 19-46 mg/dl) Placebo
59% mean reduction (95%CI 58-60), P<0.00001 Absolute reduction: 56 mg/dl (95%CI 55-57)
Sabatine MS, et al. NEJM 2017;376:1713-22
(median 0.77 mmol/L, IQR 0.49 – 1.19 mmol/L
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Key Secondary Endpoint
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
Months from Randomization
CV Death, MI, or Stroke
0 6 12 18 24 30 36
Hazard ratio 0.80 (95% CI, 0.73-0.88)
P<0.00001
Evolocumab
Placebo 7.9%
9.9%
Sabatine MS, et al. NEJM 2017;376:1713-22
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
FOURIER: LDL-cholesterol at Week 4
38 mg/dl 76 mg/dl 114 mg/dl 152 mg/dl 194 mg/dl
Guigliano RP, et al. Lancet 2017, http.://dx.doi.org/10.1016/50140-6736(17)32290-0
FOURIER
Median LDL-cholesterol at 4 Weeks by Category
Guigliano RP, et al. Lancet 2017, http.://dx.doi.org/10.1016/50140-6736(17)32290-0
FOURIER
LDL-cholesterol at 4 Weeks and Risk of Key Secondary Endpoint
Guigliano RP, et al. Lancet 2017, http.://dx.doi.org/10.1016/50140-6736(17)32290-0
Giugliano RP. ESC Congress 2017
FOURIER
Safety Events by Achieved LDL-cholesterol at 4 Weeks
Type of Event < 0.5 mmol/L n=2669 (%)
0.5-< 1.3 mmol/L
n=8003 (%)
1.3 - <1.8 mmol/L
n=3444 (%)
1.8 - <2.6 mmol/L
n=7471 (%)
≥ 2.6 mmol/L
n=4395 (%)
P-value
trend for Adjusted OR
Serious AE 23 24 24 23 23 0.30
AE leading to discontinuation
4 4 4 3 3 0. 13
Neurocognitive 1.84 1.52 1.49 0.59 1.18 0.15
New onset of Diabetes T2
8 8 9 8 8 0.48
New or
progressive cancer
2 3 3 2 2 0.72
Hemorrhagic stroke
<1 <1 <1 <1 <1 0.91
Non-CVD death1 1 1 1 1 1 0.73
Guigliano RP, et al. Lancet 2017, in press
Inclisiran
• Small interfering RNA (siRNA)
• Specific degradation of mRNA (RNA-interference)
• Suppress the mRNA-dependent synthesis of
PCSK9
ALN-PCS: Inhibition of PCSK9 mRNA
Fitzgerald K, et al. Lancet 2014;383:60-68
Lipoid Nanoparticle (LNP) for systemic iRNA in liver
Alnylam Pharmaceuticals Inc, Cambridge Massachusetts, USA
The Nobel Prize in Physiology or Medicine 2006
ORION-1
Inclisiran enkelt dose: PCSK9 endring
Ray KK, et al. NEJM 2017;376:1430-40
ORION-1
Inclisiran enkelt dose: LDL-C endring
Ray KK, et al. NEJM 2017;376:1430-40
ORION-1
Inclisiran to doser: PCSK9 endring
Ray KK, et al. NEJM 2017;376:1430-40
ORION-1
Inclisiran to doser: LDL-C endring
Ray KK, et al. NEJM 2017;376:1430-40
Next-in-line:
BEMPEDOIC ACID
Esperion Therapeutics Inc.
Bempedoic acid = ETC-1002
Binding to hepatic acyl-CoA synthetase
Pinkoski SL, et al. Nature Communications 2016. DOI:10.1038/ncomms13457
ATP-citrate lyase
ACSVL1= Acyl-CoA-Synthetase-1 (Very Long chain)
Bempedoic acid: trial design and effect on LDL-C
Thompson PD, et al. J Clin Lipidol 2015;9:205-304
LDL-C Non-HDL-C
Total-C
Effect of bempedoic acid on LDL-C after 8 weeks
Thompson PD, et al. J Clin Lipidol 2015;9:205-304
