Transcript Biochem230Presentati#28D1BB

Why study statins?
#1 & #2 selling drugs in
the world are statins –
these two drugs account
for 5% of the entire
United States spending
on drugs ($11.2 billion
dollars), since
Heart disease is the #1
killer in industrialized
countries
The poor prognosis of
homozygous FH patients
Why study statins?
Interesting clinical trial (hi)story
– some highlights
– 100 years ago Virchow
discovers “atheroma”
– 1985: NIH initiates public
health initiative to educate
patients and doctors about
dangers of
hypercholesterolemia
– First statins caused cataracts
and did not reduce plasma
cholesterol in rats – why?
– Crazy synthesis of mevinolin,
which works for heterozygous
FH
– Mevinolin is twice withdrawn
from clinical studies
Mevinolin - further proof
fermentation is a good thing
Why study statins?
Classic example of a simple biochemical
intervention that turned out to be much
more complicated than anyone thought….
Hence, the papers
Goal of the study
How is lovastatin causing a
decrease in plasma LDL
concentration?
Their approach - eliminate a possible
mechanism for lovastatin
Two possible
mechanisms of action:
1) ↓LDL by ↓formation of
apo-B
2) ↑uptake of VLDL
remnants due to ↑LDLR,
so fewer VLDL remnants
to be converted to LDL
No receptors means no VLDL or
LDL clearance by liver – if
cholesterol is lowered, lovastatin
is decreasing production of
lipoproteins
The patients
Requirements: 1) severe hypercholesterolemia
2) extremely low LDL-R activity in skin fibroblasts
3) evidence of heterozygous FH in both parents
Age
Sex
[Cholesterol]
Associated
Patient 1
6
800-1200
mg/dL*
1 wrist
xanthoma
Patient 2
6
900-1000
mg/dL*
Multiple
xanthomas
Patient 3
9
750-950
mg/dL*
Cardiac
abnormalities
(brother)
* Normal cholesterol levels are <200mg/dL; studies show levels of 240 mg/dL
put you at 2x risk for coronary events
Study protocol: 4 wks of control, 6 wks of lovastatin treatment
under controlled conditions
Results
Kinetics results
Conclusions
↓LDL must be due to LDL-R activity
↑LDL in homozygous FH probably due to
lack of uptake of VLDL by liver; transfer to
LDL by lipoprotein lipase, NOT to ↑ apo-B
synthesis in liver
A very significant decrease in plasma
[VLDL] – why?
Two theories, neither satisfactory
Theory 1: partial inhibition of cholesterol
synthesis means less VLDL
– Problem: rate of formation of LDL was not reduced;
this is not the mechanism of action of lovastatin
Theory 2: Small residue of LDL-R activity
removes remnants, but not LDL
– Problem: they’ve established these patients have
essential NO receptor activity and their experiment is
based on a lack of receptor activity
Who approved this IRB?
Is this the best way to answer
their question?
Points to consider
Isn’t an animal receptor KO model essentially the same as the
human homozygous FH model? Has this experiment already been
done?
Is it appropriate to use human subjects to confirm a drug does NOT
work?
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What if you take them off their current treatment for months?
What if you feed them a diet that further complicates their illness?
What if they are six-year-old children?
What if previous studies seem to indicate that the drug will not work?
What if you will be using radioactive iodine isotopes? (invasiveness of
study)
How would you pitch this study to a family? (i.e., this probably won’t
work, but what’s important is why?)
Is obtaining consent from a 6-yr-old feasible?
Does the prognosis of the patients make a difference?