djelovanjem na LDL kolesterol - Ruđer Bošković Institute · djelovanjem na LDL kolesterol Prof.dr.sc. Luka Zaputović, dr.med. Zavod za kardiovaskularne bolesti Klinički bolnički

Nove mogućnosti u prevenciji ateroskleroze djelovanjem na LDL kolesterol

Prof.dr.sc. Luka Zaputović, dr.med.

Zavod za kardiovaskularne bolesti

Klinički bolnički centar Rijeka

Medicinski fakultet, Sveučilište u Rijeci

Godišnji kongres Hrvatskog društva za vaskularnu kirurgiju

Opatija, 23. svibnja, 2019.

2

High LDL-C levels increase risk across all types of ASCVD

Incidence (per 1,000 person-years) per LDL-C Quartile

Mean LDL-C quartiles (mmol/L)

1 2 3 4

2.7 3.6 4.2 5.3

Person –years 64,431 64,547 62,053 63,574

Incidence (per 1,000 person years)

CAD (N = 2332) 5.77 8.24 10.09 12.62

Ischemic stroke (N = 268) 0.67 1.05 1.10 1.40

Hemorrhagic stroke (N = 117) 0.45 0.43 0.45 0.50

Abdominal aneurysm (N = 143) 0.42 0.56 0.58 0.69

PAD (N = 227) 0.70 0.67 1.05 1.16

ASCVD = atherosclerotic cardiovascular disease; CAD = coronary artery disease; LDL-C = low-density lipoprotein cholesterol;

PAD = peripheral arterial disease.

Stoekenbroek RM, et al. Eur Heart J. 2016;37:880-889.

2016 ESC/EAS Guidelines: pharmacological treatment of LDL cholesterol

2016 ESC/EAS Dyslipidaemias Guidelines: recommendations for PCSK9 inhibitors

PCSK9 inhibitors are recommended in: • HeFH pateints: “Treatment with a PCSK9 antibody should be considered in FH patients with CVD or with other factors putting them at very high-risk for CHD, such as other CV risk factors, family story, high Lp(a) or statin

intolerance.” IIa C

• ACS/PCI patients “If the LDL-C target is not reached with the highest tolerable statin dose and/or ezetimibe, PCSK9 inhibitors may be considered on top of lipid-lowering therapy; or alone or in combination with ezetimibe in statin

intolerant patients or in whom a statin is contra-indicated. IIb C

HZZO Guidelines for PCSK9 inhibitors

Plasma LDL-C is controlled by hepatic Low-Density Lipoprotein Receptor (LDLR) levels

1. Brown MS, et al. Proc Natl Acad Sci USA. 1979;76:3330-3337. 2. Steinberg D, et al. Proc Natl Acad Sci USA. 2009;106:9546-9547.

3. Brown MS, et al. Science. 1986;232:34-47.

LDL = low density lipoprotein; LDLR = low-density lipoprotein receptor.

Recycling of LDLR

Increased LDLR

surface concentration

LDL

particles

LDLR

LDLR

PCSK9

3. C-terminus 2. Prodomain 1. Catalytic

domain

PCSK9 is a protease predominantly secreted by the liver and a regulator of LDL metabolism1

• A serine proprotein convertase1

• Expressed in hepatocytes, kidney

mesenchymal cells, intestinal

ileum and colon epithelia, CNS2

• Regulates hepatic LDLRs, which

bind and internalize LDL particles3

1

2

3

CNS = central nervous system; LDL = low-density lipoprotein; LDLR = low-density lipoprotein receptor;

PCSK9 = proprotein convertase subtilisin/kexin type 9.

1. Abifadel M, et al. Hum Mutat. 2009;30:520-529. 2. Seidah NG, et al. Proc Natl Acad Sci U S A. 2003;100:928-933.

3. Horton JD, et al. J Lipid Res. 2009;50 Suppl:S172-S177.

Evolocumab is a fully human monoclonal antibody against PCSK9 and inhibits PCSK9/LDLR interaction, thereby lowering plasma LDL-C levels

1. Chan JC, et al. Proc Natl Acad Sci USA. 2009;106:9820-9825.

2.Stein EA, et al. Drugs of the Future. 2013;38:451-459

Evolocumab

Increased LDLR concentration

LDLR recycling LDLR

PCSK9

LDL-R recycling

restored

LDL = low density lipoprotein; LDLR = low-density lipoprotein receptor; PCSK9 = proprotein convertase subtilisin/kexin type 9.

Evolocumab and clinical outcomes in patients with cardiovascular disease

Sabatine MS, et al. N Engl J Med. 2017;376:1713-1722.

FOURIER: Further cardiovascular OUtcomes Research with PCSK9

Inhibition in subjects with Elevated Risk

• Designed to test whether patients with established cardiovascular

disease who are already on optimal cardiovascular therapy,

including high to moderate intensity statins, benefit from maximal

LDL-C reduction with evolocumab

• Additionally, will evaluate the clinical efficacy and safety of achieving

unprecedented levels of low LDL-C with evolocumab

• Global randomized, placebo-controlled, double-blind trial

(n = 27,564; 49 countries; 1,242 sites)

PCSK9, proprotein convertase subtilisin/kexin type 9.

Sabatine MS, et al. Am Heart J. 2016;173:94-101.


Evolocumab Outcomes Trial: Objective

Evolocumab Outcomes Trial: Study design overview

Screening

• Age 40–85 years

• MI, stroke, or PAD

• Additional risk factors (one

major or two minor)

• Optimal background lipid

therapy (including effective dose

of statin ezetimibe)

• LDL-C ≥ 1.81 mmol/L or

non–HDL-C ≥ 2.59 mmol/L

Evolocumab SC 140 mg Q2W or 420 mg QM

(per subject preference)

n ~ 13,750

Placebo SC Q2W or QM

(per subject preference)

n ~ 13,750 R

an

do

miz

ati

on

1:1

En

d o

f S

tud

y (

EO

S)

Maximum approximately 15 weeks D1 W4 W12 W24 Q24W Number of

key 20

endpoints

achieved

CV, cardiovascular; D, day; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol;

MI, myocardial infarction; PAD, peripheral artery disease; Q2W, every 2 weeks; Q24W, every 24 weeks; QM, every month;

SC, subcutaneous; UA, unstable angina; W, week.

Sabatine MS, et al. Am Heart J. 2016;173:94-101.

Median LDL-C levels over time: All Patients

LDL-C was significantly reduced in the evolocumab group (median: 0.78 mmol/L)

including 42% who achieved levels ≤ 0.65 mmol/L vs < 0.1% in the placebo group

Data shown are median values with 95% confidence intervals in the two arms; ITT.


13,251 13,151 12,954 12,596 12,311 10,812 6,926 3,352 790 13,779 Placebo 13,288 13,144 12,964 12,645 12,359 10,902 6,958 3,323 768 13,784 Evolocumab

No. at risk

4 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

LD

L C

ho

leste

rol

(mm

ol/L

)

Weeks

59% mean reduction (95% CI 58-60), P < 0.001

Absolute reduction: 1.45 mmol/L (95% CI 1.43-1.47)

2.4

2.2

2.0

1.8

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0

2.6

Placebo

Median 2.38 mmol/L

Evolocumab

Median 0.78 mmol/L

Primary endpoint: composite of CV death, MI, stroke, hospitalization for UA, or coronary revascularization

HR 0.85 (95% CI 0.79 to 0.92); P < 0.001

CV = Cardiovascular; MI = Myocardial infarction; UA = Unstable angina; HR = Hazard ratio


6.0

10.7

14.6

5.3

9.1

12.6

No. at Risk Placebo 13,780 13,278 12,825 1 1,871 7,610 3,690 686 Evolocumab 13,784 13,351 12,939 12,070 7,771 3,746 689

Cu

mu

lati

ve I

ncid

en

ce (

%) Placebo

Evolocumab

0

2

4

6

8

10

12

14

16

0 6 18 12 24 36 30 Months

3.7

6.8

9.9

Key secondary endpoint: Composite of CV death, MI, or stroke

HR 0.80 (95% CI 0.73 to 0.88); P < 0.001

No. at Risk Placebo Evolocumab

Cu

mu

lati

ve I

ncid

en

ce (

%) Placebo

Evolocumab

Months

0

2

4

6

8

9

10

11

0 6 18 12 24 36 30

1

3

5

7

13,780 13,449 13,142 12,288 7,944 3,893 731 13,784 13,501 13,241 12,456 8,094 3,935 724

3.1

5.5

7.9

CV = Cardiovascular; MI = Myocardial infarction; HR = Hazard ratio


PRIMARY ENDPOINT: Event Rate (%) KEY SECONDARY ENDPOINT: Event Rate (%)

Patients Evo Pbo HR (95% CI) HR (95% CI) Pinteraction Evo Pbo HR (95% CI) HR (95% CI) Pinteraction

OVERALL 27564 9.8 11.3 0.85 (0.79-0.92) 5.9 7.4 0.80 (0.73-0.88)

Age 0.90 0.79

<65 15310 9.9 11.4 0.86 (0.78-0.94) 5.5 6.9 0.79 (0.69 -0.90)

≥65 12254 9.6 11.2 0.85 (0.76-0.95) 6.4 7.9 0.81 (0.71 -0.92)

Sex 0.48 0.44

Female 6769 8.1 9.9 0.81 (0.69-0.95) 5.1 6.7 0.74 (0.61 -0.90)

Male 20795 10.3 11.8 0.86 (0.80-0.94) 6.2 7.5 0.81 (0.73 -0.90)

Race 0.036 0.048

Caucasian 23458 10.1 11.4 0.88 (0.81-0.95) 6.0 7.2 0.83 (0.75-0.92)

Non-Caucasian 4106 8.0 11.2 0.70 (0.57-0.86) 5.3 8.1 0.64 (0.50-0.81)

Region 0.15 0.012

North America 4571 12.9 16.5 0.77 (0.66 -0.90) 6.7 10.6 0.62 (0.51-0.76)

Europe 17335 9.6 10.5 0.91 (0.83 -1.00) 6.0 6.7 0.90 (0.80-1.01)

Latin America 1823 8.8 10.1 0.85 (0.63-1.15) 5.5 6.4 0.85 (0.58-1.24)

Asia/Pacific 3835 7.1 9.6 0.73 (0.58-0.91) 4.7 7.0 0.67 (0.51-0.88)

Efficacy in key subgroups: Primary and key secondary endpoints


(Supplementary Figure S5)

Primary and secondary composite endpoint results were

consistent across all key subgroups

0.5 1.0 2.0

Evolocumab better Placebo better

0.5 1.0 2.0


PRIMARY ENDPOINT: Event Rate (%) KEY SECONDARY ENDPOINT: Event Rate (%)

Patients Evo Pbo HR (95% CI) HR (95% CI) Pinteraction Evo Pbo HR (95% CI) HR (95% CI) Pinteraction

OVERALL 27564 9.8 11.3 0.85 (0.79-0.92) 5.9 7.4 0.80 (0.73-0.88)

Type of disease 0.19 0.38

MI alone 19113 9.6 10.8 0.88 (0.80-0.96) 5.2 6.4 0.80 (0.71 -0.90)

Stroke alone 3366 6.0 8.5 0.70 (0.54-0.90) 5.0 6.5 0.77 (0.58 -1.02)

PAD alone 1505 6.7 9.9 0.67 (0.47-0.96) 4.5 7.8 0.57 (0.38-0.88)

Polyvasculardisease 3563 15.5 17.4 0.88 (0.75-1.03) 11.1 12.9 0.86 (0.71-1.04)

Baseline LDL-C 0.69 0.96

Q1 (<2.07 mmol/L) 6961 8.3 10.4 0.80 (0.69 -0.93) 5.1 6.6 0.78 (0.64-0.95)

Q2 (2.07-<2.38 mmol/L) 6886 9.3 11.2 0.82 (0.71 -0.96) 5.4 6.8 0.79 (0.65-0.96)

Q3 (2.38 -2.82 mmol/L) 6887 10.2 11.3 0.89 (0.77 -1.03) 6.3 7.9 0.79 (0.66-0.94)

Q4 (>2.82 mmol/L) 6829 11.2 12.5 0.89 (0.77-1.02) 6.9 8.2 0.83 (0.70-0.99)

Baseline statin intensity 0.37 0.33

High 19103 10.2 11.6 0.87 (0.80-0.95) 6.1 7.4 0.82 (0.74 -0.92)

Not High 8461 8.8 10.7 0.80 (0.70-0.92) 5.5 7.2 0.74 (0.63 -0.88)

Ezetimibe 0.26 0.76

Yes 1440 13.4 13.6 0.98 (0.74-1.31) 7.4 9.8 0.74 (0.52-1.06)

No 26124 9.5 11.2 0.84 (0.78-0.91) 5.8 7.2 0.80 (0.73-0.88)

Initial Dosing Regimen 0.83 0.89

Every 2 weeks 24774 9.9 11.5 0.85 (0.79 -0.92) 6.0 7.5 0.80 (0.72-0.88)

Monthly 2790 8.6 10.3 0.82 (0.64 -1.04) 5.2 6.4 0.80 (0.59-1.09)

Efficacy in key subgroups: Primary and key secondary endpoints continued



0.5 1.0 2.0


0.5 1.0 2.0


Primary and secondary composite endpoint results were consistent across all key subgroups

Association of LDL-C levels and CV events

P<0.0001 Q4

Q3

Q2

Q1

Q4 Q3

Q2

Q1

Placebo

Evolocumab

13%

12%

11%

10%

9%

8%

7%

6%

5%

Achieved LDL Cholesterol (mmol/L)

Card

iovascu

lar

Death

, M

I, o

r S

tro

ke

Patients divided by quartile of baseline LDL-C and by treatment arm

Sabatine MS, et al. American College of Cardiology – 66th Annual Scientific

Session Late-Breaking Clinical Trial. Washington, D.C. March 17, 2017.

2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 2.6 3.2 3.0 2.8

Landmark analysis of primary endpoint

Year 1: RRR 12% > Year 1: RRR 19%

Longer duration of treatment and follow up suggests larger risk reduction

Evolocumab

Cu

mu

lati

ve

In

cid

en

ce

(%

)

0%

2%

4%

6%

8%

10%

0 90 180 270 360 Days No. at Risk

Placebo 13780 13542 13282 13044 12834 Evolocumab 13784 13563 13358 13137 12950

Placebo

Hazard ratio 0.88

(95% CI, 0.80-0.97)

13524 12467 8080 3928 891 13548 12598 8204 3942 888

0%

2%

4%

6%

8%

10%

360 540 720 900 1080

Cu

mu

lati

ve

In

cid

en

ce

(%

)

Days

Placebo

Evolocumab

Hazard ratio 0.81

(95% CI, 0.73-0.89)

Landmark analyses were performed in which patients who were alive and in follow-up at the start

of the period of interest formed the group at risk.



13780 13617 13453 13291 13148 13784 13636 13505 13357 13248

13524 12609 8250 4056 925 13548 12721 8359 4051 911

0%

2%

4%

6%

8%

360 540 720 900 1080

Cu

mu

lati

ve

In

cid

en

ce

(%

)

Days

Placebo

Evolocumab

Hazard ratio 0.75

(95% CI, 0.66-0.85)

Landmark analysis of key secondary endpoint

> Year 1: RRR 25%

Evolocumab

Cu

mu

lati

ve

In

cid

en

ce

(%

)

0%

2%

4%

6%

8%

0 90 180 270 360 Days No. at Risk

Placebo Evolocumab

Placebo

Hazard ratio 0.84

(95% CI, 0.74-0.96)

Longer duration of treatment and follow up suggests larger risk reduction

Year 1: RRR 16%

Landmark analyses were performed in which patients who were alive and in follow-up at the start

of the period of interest formed the group at risk.



Adverse events in the safety population*

Adverse Events, n (%) Evolocumab (N = 13,769)

Placebo (N = 13,756)

Any 10,664 (77.4) 10,644 (77.4)

Serious 3,410 (24.8) 3,404 (24.7)

Thought to be related to the study agent and leading to discontinuation of study regimen 226 (1.6) 201 (1.5)

No notable differences in the rate of AEs, SAEs, or AEs leading to discontinuation

*Safety evaluations included all randomized patients who received at least one dose of study treatment and for whom post-dose data are available. Sabatine MS, et al. N Engl J Med. 2017;376:1713-1722.

PAD sub-analysis

Bonaca MP, et al. Circulation. 2017. November 13. doi:10.1161/CIRCULATIONAHA.117.032235.

[Epub ahead of print].

Baseline characteristics by history of PAD

All p-values < 0.05 except history of atrial fibrillation (p=0.50).

CABG = coronary artery bypass grafting; CHF = congestive heart failure; IQR = interquartile range; MI = myocardial infarction;

PAD = peripheral artery disease; PCI = percutaneous coronary intervention; TIA = transient ischemic attack.



Of the patients with a history of PAD, ~50% had a history of prior MI and ~19% had history of prior stroke/TIA

No PAD N = 23,922

PAD N = 3,642 (13%)

Age, median (IQR) 63 (56, 69) 64 (58, 69)

Female sex, n (%) 5743 (24.0) 1026 (28.2)

Body Mass Index, median (IQR) 29 (26, 32) 29 (26, 32)

Caucasian, n (%) 20,156 (84.3) 3,302 (90.7)

History Hypertension, n (%) 18,993 (79.4) 3,091 (84.9)

Current Smoker, n (%) 6,451 (27.0) 1,326 (36.4)

Renal Insufficiency, n (%) 1,323 (5.5) 340 (9.3)

History of Myocardial Infarction, n (%) 20,539 (85.9) 1,812 (49.8)

History of Stroke/TIA, n (%) 5,101 (21.3) 685 (18.8)

PAD with No Prior MI or Stroke 0 1,505 (41.3)

History of Atrial Fibrillation, n (%) 2,022 (8.5) 320 (8.8)

History of Diabetes, n (%) 8,501 (35.5) 1,580 (43.4)

History of CHF, n (%) 5,625 (23.5) 769 (21.1)

Prior CABG, n (%) 4,387 (18.4) 839 (23.0)

History of PCI, n (%) 14,029 (58.7) 1,444 (39.7)

Compared to those without a history of PAD, patients with PAD tended to be:

• Older • Hypertensive • Current smoker • With renal insufficiency • Diabetic

LD

L-C

(m

g/d

L)

Evolocumab

0

10

20

30

40

50

60

70

80

90

100

0 4 12 24 48 72 96 144

Weeks

Placebo

Median 0.8 mmol/L

Median 2,35 mmol/L

120

Evolocumab Placebo

LDL-C reduction with evolocumab remained stable through week 144 in patients with a history of PAD

IQR = interquartile range; LDL-C = low-density lipoprotein cholesterol; PAD = peripheral artery disease.



LDL-C concentrations over time in patients with history of PAD

Reduction of Major Adverse Limb Events (MALE) in the full cohort

Evolocumab reduced the risk of MALE by 42% in the full cohort HR (95% CI) are shown.

MALE defined as acute limb ischemia, major amputation (AKA or BKA), or urgent peripheral revascularization for ischemia.

AKA = amputations above the knee; ALI = acute limb ischemia; BKA = amputations below the knee; HR = hazard ratio;

PAD = peripheral artery disease.



All Patients N = 27,564

Days from Randomization

0.45%

0.27%

HR: 0.58 (0.38 – 0.88) P = 0.0093

0%

0.1%

0.2%

0.3%

0.4%

0.5%

0 180 360 540 720 900

Ris

k o

f M

AL

E

Evolocumab

Placebo

Reduction of Major Adverse Limb Events (MALE) by history of PAD

Evolocumab reduced the relative risk of MALE in patients with and without a history of PAD (Pinteraction = 0.29)

MALE defined as acute limb ischemia, major amputation (AKA or BKA), or urgent peripheral revascularization for ischemia.

AKA = amputations above the knee; ALI = acute limb ischemia; BKA = amputations below the knee; HR = hazard ratio;

PAD = peripheral artery disease.



Ris

k o

f M

AL

E

Evolocumab

Placebo

0%

0.02%

0.06%

0.10%

0.14%

0.18%

0 180 360 540 720 900

Patients without PAD N = 23,922


0.16%

0.076%

HR: 0.37 (0.16 – 0.88) P = 0.0197

0.04%

0.08%

0.12%

0.16%

0%

0.5%

1.0%

1.5%

2.0%

2.5%

0 180 360 540 720 900

Patients with PAD N = 3,642

2.4%

1.5%

HR: 0.63 (0.39 – 1.03) P = 0.063


Reduction of Major Adverse Limb Events (MALE) in patients with history of PAD without prior MI or stroke

Evolocumab reduced the risk of MALE by 57% in patients with a history of PAD and no prior MI or stroke

Ris

k o

f M

AL

E

0%

0.5%

1.0%

2.0%

3.0%

0 90 180 270 900

PAD Without Prior MI or Stroke N = 1,505

1.5%

2.5%

360 540 720 450 630 810

2.6%

1.3%

Evolocumab

Placebo

HR (95% CI) are shown. MALE defined as acute limb ischemia, major amputation (AKA or BKA), or urgent peripheral revascularization for ischemia.

AKA = amputations above the knee; ALI = acute limb ischemia; BKA = amputations below the knee; CI = confidence interval;

HR = hazard ratio; MI = myocardial infarction; NNT = number needed to treat; PAD = peripheral artery disease




HR: 0.43 (0.19 – 0.99)

P = 0.042

Reduction of Composite of MALE or MACE by history of PAD

MACE or MALE Composite


15.0%

10.9%

PAD HR: 0.73 (0.60 – 0.88)

P = 0.0014

No PAD HR: 0.80 (0.72 – 0.89)

P < 0.001

PAD 4.1% ARR NNT 25

No PAD 1.5% ARR NNT 67

0 90 180 270 360 450 540 630 720 810 900 0%

2%

4%

6%

8%

10%

12%

14%

16%

7.8%

6.3%

Evolocumab

Placebo

Ris

k o

f M

AL

E o

r M

AC

E

PAD = Solid lines, n = 3,642; No PAD = Dotted lines, n= 23,922. HR (95% CI) are shown. MALE defined as acute limb ischemia, major amputation (AKA or

BKA), or urgent peripheral revascularization for ischemia. MACE defined as CV death, MI or stroke. AKA = amputations above the knee; ARR = absolute

risk reduction; CV = cardiovascular; ALI = acute limb ischemia; BKA = amputations below the knee; HR = hazard ratio; MI = myocardial infarction;

MACE = major adverse cardiovascular event; MALE = major adverse limb event; NNT = number needed to treat; PAD = peripheral artery disease.

Bonaca MP, et al. Circulation. 2017. November 13. doi:10.1161/CIRCULATIONAHA.117.032235. [Epub ahead of print].

Relative risk reduction (RRR) for the composite of MALE or MACE was similar in patients with and without a history of PAD (Pinteraction = 0.39), with a numerically greater absolute risk

reduction (ARR) observed in PAD due to higher absolute risk in these patients

Adjusted relationship between achieved LDL-C at 1 month and MALE in the overall population. P=0.026 for the beta coefficient. See Backup for

Supplemental Results. MALE defined as acute limb ischemia, major amputation (AKA or BKA), or urgent peripheral revascularization for ischemia.

MACE defined as CV death, MI or stroke. AKA = amputations above the knee; ALI = acute limb ischemia; BKA = amputations below the knee;

CV = cardiovascular; LDL-C = low-density lipoprotein cholesterol; MACE = major adverse cardiovascular event; MI = myocardial infarction.


Achieved LDL-C and Major Adverse Limb Event (MALE) outcomes in the full cohort

Lower achieved LDL-C was roughly linearly associated with lower risk of MALE with no apparent plateau

0 50 100 150

LDL-C (mg/dL) at 1 month

0.000

0.0050

0.0075

0.0100

0.0125 P = 0.026 for beta coefficient

0.0025

Ad

jus

ted

Even

t R

ate

(P

rob

ab

ilit

y)

Adverse events and laboratory results in patients with history of PAD

In patients with a history of PAD, incidence of AEs and serious AEs was similar between evolocumab and placebo groups; few AEs lead to treatment discontinuation (1.3% evolocumab vs. 1.5% placebo, P = 0.57)

Placebo N = 1,780

Evolocumab N = 1,856

Adverse events, n (%)

Any 1,408 (79.1%) 1,481 (79.8%)

Serious 624 (35.1%) 601 (32.4%)

Thought to be related to the study agent and leading to discontinuation of study regimen

27 (1.5%) 24 (1.3%)

Injection-site reaction 32 (1.8%) 26 (1.4%)

Allergic reaction 47 (2.6%) 54 (2.9%)

Muscle-related event 79 (4.4%) 94 (5.1%)

Rhabdomyolysis 1 (0.1%) 2 (0.1%)

Cataract 43 (2.4%) 24 (1.3%)

Adjudicated case of new-onset diabetes* 67 (6.7%) 80 (8.3%)

Neurocognitive event 31 (1.7%) 28 (1.5%)

Laboratory results, n (%)†

Aminotransferase level > 3x ULN 31 (1.8%) 27 (1.5%)

Creatine Kinase level > 5 ULN 15 (0.9%) 5 (0.3%)

*Denominator for new-onset diabetes is 996 for placebo and 963 for evolocumab. †Denominator for lab results is 1,747 for placebo and 1,812 for evolocumab. P-value

was calculated by chi-square tests. All p-values > 0.05 except nominal p = 0.0119 for cataracts and 0.0201 for CK > 5. AE = adverse event; CK = creatine kinase;

PAD = peripheral artery disease; ULN = upper limit of the normal range.


Zaključak

• Evolokumab značajno smanjuje kardiovaskularne ishode u prethodno optimalno liječenih bolesnika s aterosklerotskom kardiovaskularnom bolešću različitih lokalizacija

• Terapijski učinak evolokumaba konzistentno je prisutan u svim podskupinama bolesnika

• Nema negativnih sigurnosnih signala, sigurnost lijeka slična je placebu, čak i u bolesnika s postignutim vrlo niskim vrijednostima LDL-kolesterola

• Najveću kliničku korist imaju najrizičniji bolesnici (dijabetičari, polivaskularni i bolesnici s perifernom arterijskom bolešću)

Documents

djelovanjem na LDL kolesterol - Ruđer Bošković Institute · djelovanjem na LDL kolesterol Prof.dr.sc. Luka Zaputović, dr.med. Zavod za kardiovaskularne bolesti Klinički bolnički