kolesterol venn eller fiende? - universitetet i bergen · evacetrapib: tranformere ldl hdl 49 12...
TRANSCRIPT
1
Kolesterol – venn eller fiende?
Einar Sletten, professor emeritus, Kjemisk institutt, UiB
2
Kolesterol
3
Kolesterolnivå – målemetodeHDL: High-Density-Lipoprotein; LDL: Low-Density-Lipoprotein
4
i) Total kolesterol: kolesteryl ester + H2O hydrosylase + kolesterol + fettsyre
ii) HDL – kolesterol (Sentrifugere ut HDL)
iii) Triglyserid (TG) triglyserid + lipase glyserol + fettsyre
iv) LDL - kolesterol = [total kol] - [HDL-kol] - [TG]/5
5
Lever
80 %
HDL: High Density Lipoprotein transport frå celle til lever
LDL: Low Density Lipoprotein transport frå lever til celle
6
Lipoprotein: HDL og LDL
7
8
9
NMR-spektra
Lipoprotein
Proton Nuclear Magnetic Resonance Spectroscopy of Serum
Lipoproteins in Rabbits with Implanted VX-2 Carcinoma.
Gro Gadeholt, Svetlana Kruse, Line Halsteinslid and Einar Sletten
Eur. J. Cancer, Vol. 26, No. 5, pp. 61141S. 1990.
Kolesterol – hjerte-kar-sjukdom (HKS)
• 1840 Karl von Rokitansky «plaques» i blodårer
• 1904 Felix Marchand artherosclerosis
• 1913 Nikolai Anitschkov kaninforsøk, kolesterol
• 1953 Ancel Keys advarsel mot fett
10
Fettsyrer
α
ωOmega-3 fettsyre
12
Triglyserid (fett)
13
Ancel Keys - mannen som lurte oss trill rundt
14
Samanheng mellom fettrik diett og hjerte-kar sjukdom?
1958-1964
7 land
15
”Saturated fats in the diet clogged arteries
and caused heart disease”
1961
16
Drastisk skifte i folks diettvaner basert på Ancel Keys
Komplett datasett (22 land)
17
18
«Scientists were wrong about saturated fats.
They don’t cause heart disease after all»
2014
19
Eating fat is good for you:
Doctors change their minds after 40 years
The obsession with a low-fat diet has “paradoxically
increased” the risk of heart disease.
Cardiologist Dr Aseem Malhotra
20
Ny studie, reviderte data, (1968 -1973),
9 000 pasientar på eldresenter i Minnesota.
1. Diett med umetta fett: 13 % lægre kolesterol nivå enn diett
med metta fett
2. “Surprising, the low cholesterol was actually associated
with an increased risk of dying”
21
221972
Kolesterol – eit svært viktig molekyl !
• Cellemembranar 50% kolesterol
• Hjernen 25 % kolesterol
• Hormonar: cortisol, aldosteron, progesteron, estrogen, testosteron
• Vitaminar : syntese av A og D
• Co-enzym Q10
• Isolerer nervetrådar.
• Lågt kolesterolnivå kan gi helseproblem
• Eldre med høgt kolesterolnivå har best hukommelse!
Am. J. Geriatr Psychiatry Geriatr, 2008 Sep;16(9):78.
.
23
24
25
Avleiring i kransarterier «plaque»
LDL
26Landé K, Sperry, W.: Arch Pathol 1936, 22:301-312.
Aorta-
fettinnhald
27
• Hypotese: Kolesterol årsak til «plaque» i kransarterier
• Legemiddelindustrien foreslår: kolesterolnivå < 2-3 mmol
• Gjennomsnitt Norge: 5,6 mmol
• Statinar: Kolesterol-reduserande legemiddel
• Tilråding (USA): Start behandling i 8-årsalderen!
28
National Cholesterol Education Program (NCEP).
Rettningslinjer for bruk av statinar.
«All members of the 2004 guideline participants had received
payments and/or grant funds from the following organisations»:
Abbott
Astra Zeneca
Bayer
Bristol-Myers Squibb
Glaxo
Merck
Pfizer
Novartis
Procter & Gamble
SmithKline
Statinar: Reduserer produksjon av kolesterol
29
30
Syntese – 25 steg!
31
32
Absolutt og relativ risiko
Eksempel: risiko for treff av lyn
Utendørs: 0.000002 %
Innandørs: 0.000001%
Absolutt Risiko Reduksjon: 0.000001%
Relativ Risiko Reduksjon: 50 %
33
Behandling med Lipitor (statin)
Antal fatal non-fatal totalt
Lipitor 5168 40 60 100 ---> 1.9 %
Placebo 5237 46 108 154 ---> 3.0 %
Absolutt Risiko Reduksjon:............. 3.0 – 1.9 = 1.1 %
Relativ Risiko Reduksjon:.......(1.1/3.0) x 100 = 36.6 %
Statinbehandlig: «to save lives» ?
34
35
Bi-effektar ved statinbehandling
Food and Drug Administration (FDA)
Drug Safety Communication: Important safety label changes
to cholesterol-lowering statin drugs (2012)
1. Muscle pain and damage
2. Liver damage
3. Neurological side effects
4. Polyneuropati
5 Increased blood sugar or type 2 diabetes
Increased risk of diabetes with statin treatment is
associated with impaired insulin sensitivity and insulin
secretion. M, Laakso et. al. Journal Diabetologia (2015)
36
Loss of Life Expectancy Due to Various Causes
Causes Dagar
Being unmarried-male 3500
Cigarette smoking-male 2250
Heart disease 2100
Being unmarried-female 1600
Being 30% overweight 1300
Cancer 980
20% overweight 900
Motor vehicle accidents 207
Pneumonia-influenza 141
Alcohol (U.S. average) 130
Diabetes 95
Being murdered (homicide) 90
Drinking coffee 6
Bicycling 5
Nuclear accident 0,002
37
Statin i Norge
start punkt
38
39
(mg)
220 mg = 5.7 mmol
MONICA: 10 millionar personar, 21 land, 10 års periode
Per 100 000
40
Kolesterol
mmol
Heart disease rates in men aged 35-74
MONICA project
Frankrike
Spania
41
“The largest ever cardiology study has failed to
find a link between heart attacks and high
cholesterol levels.”
42
i) EU: “New regulations on clinical trials in 2004”
iii) “After 2004 all clinical trials, performed by scientists free of
conflict of interest reported that statins were effective in
lowering LDL-C but no significant beneficial effects were
observed for the prevention of CHD”
USA Dietary Guidelines
Advisory Committee (2015)
“there is no scientific evidence
of a connection between
cholesterol intake and heart
disease”.
44
Primary
prevention
Secondary
prevention
45
i) Statinar Nr. 1 legemiddel på bestseljar lista
ii) Pfitzer (Lipitor) (1997-2011): $125 milliardar
iii) AstraZeneca’s Crestor: $5.2 milliardar dollar i 2013
iv) Lobbying (2005): $800 millionar til valgkampbidrag
v) Behandling: 19.2 % , (45-64); 39.6 %, (65-74); 44.3 % >75 år
vi) Anbefaling: 97 % alle menn (66 – 75 år) bør ta statinar!
vi) Statin bruk: Norge 1 av 5
46
Kan vi lite på informasjon
frå Wikipedia?
«Pharmageddon»
47
Nye medikament
48
Evacetrapib: Tranformere LDL HDL
49
12 000 CAD pasientar over tre år (avslutta oktober 2015)
• HDL auka med 130 %
• LDL avtok med 37%
• Konklusjon: "Here we have a paradox. The drug more than doubled
HDL and lowered LDL, but had no effect on cardiac events.” Steve
Nissen, chairman of Cardiovascular Medicine at Cleveland Clinic
Årsaker til hjarte-kar-sjukdom ?
• Skade på arteriene pga. inflammasjon
• Homocysteine nivå ?
• STRESS
• «Not everything that can be measured, matters, and
not everything that matters can be measured»
Albert Einstein
50
51
"The great tragedy of science -- the slaying of a
beautiful hypothesis by an ugly fact."
-- Thomas Huxley
1825-1895
Takk for meg !
The Great Cholesterol Con:
The Truth About What Really Causes Heart Disease and How
to Avoid It.
Malcolm Kendrick (2008)
• www.thincs.org
52
53
All forsking er ikkje god forsking
Ein gjennomgang av den mest siterte medisinske forskinga,
viste at mellom ein tredel og halvparten av konklusjonane
seinare blei motbevist.
Folk må lære seg å være kritisk til påstander om at noko er
vitskapeleg bevist, enten det gjeld helsestoff eller
klimaendringar
,
54
“Historically, the claim of consensus has been the first
refuge of scoundrels; it is a way to avoid debate by
claiming that the matter is already settled. Whenever
you hear the consensus of scientists agrees on
something or other, reach for your wallet, because
you’re being had.” – Michael Crichton
55
N Engl J Med. 2006 Apr 13;354(15):1578-88. Epub 2006 Mar 12.
Homocysteine lowering and cardiovascular events after acute
myocardial infarction.
Bønaa KH1, Njølstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T,
Wang H, Nordrehaug JE, Arnesen E, Rasmussen K; NORVIT Trial
Investigators.
.