Why study statins?Why study statins?

#1 & #2 selling drugs in #1 & #2 selling drugs in the worldthe world are statins – are statins – these two drugs account these two drugs account for 5% of the entire for 5% of the entire United States spending United States spending on drugs ($11.2 billion on drugs ($11.2 billion dollars), sincedollars), sinceHeart disease is the #1 Heart disease is the #1 killerkiller in industrialized in industrialized countriescountriesThe The poor prognosispoor prognosis of of homozygous FH patientshomozygous FH patients

Why study statins?Why study statins?

Interesting clinical trial (hi)storyInteresting clinical trial (hi)story – some highlights– some highlights– 100 years ago Virchow 100 years ago Virchow

discovers “atheroma”discovers “atheroma”– 1985: NIH initiates public 1985: NIH initiates public

health initiative to educate health initiative to educate patients and doctors about patients and doctors about dangers of dangers of hypercholesterolemiahypercholesterolemia

– First statins caused cataracts First statins caused cataracts and did not reduce plasma and did not reduce plasma cholesterol in rats – why?cholesterol in rats – why?

– Crazy synthesis of mevinolin, Crazy synthesis of mevinolin, which works for heterozygous which works for heterozygous FHFH

– Mevinolin is twice withdrawn Mevinolin is twice withdrawn from clinical studiesfrom clinical studies

Mevinolin - further proof fermentation is a good thing

Why study statins?Why study statins?

Classic example of a simple biochemical Classic example of a simple biochemical intervention that turned out to be much intervention that turned out to be much more complicated than anyone thought….more complicated than anyone thought….

Hence, the papersHence, the papers

Goal of the studyGoal of the study

How is lovastatin causing a How is lovastatin causing a decrease in plasma LDL decrease in plasma LDL

concentration?concentration?

Their approach - eliminate a possible Their approach - eliminate a possible mechanism for lovastatinmechanism for lovastatin

Two possible Two possible mechanisms of actionmechanisms of action::

1)1) ↓↓LDL by ↓formation of LDL by ↓formation of apo-Bapo-B

2)2) ↑↑uptake of VLDL uptake of VLDL remnants due to ↑LDLR, remnants due to ↑LDLR, so fewer VLDL remnants so fewer VLDL remnants to be converted to LDLto 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 patientsThe patients

RequirementsRequirements: : 1) severe hypercholesterolemia1) severe hypercholesterolemia 2) extremely low LDL-R activity in skin fibroblasts2) extremely low LDL-R activity in skin fibroblasts 3) evidence of heterozygous FH in both parents3) evidence of heterozygous FH in both parents

AgeAge SexSex [Cholesterol][Cholesterol] AssociatedAssociated

Patient 1Patient 1 66 800-1200 800-1200 mg/dL*mg/dL*

1 wrist 1 wrist xanthomaxanthoma

Patient 2Patient 2 66 900-1000 900-1000 mg/dL*mg/dL*

Multiple Multiple xanthomasxanthomas

Patient 3Patient 3 99 (brother)(brother) 750-950 750-950 mg/dL*mg/dL*

Cardiac Cardiac abnormalitiesabnormalities

* 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

ResultsResults

Kinetics resultsKinetics results

ConclusionsConclusions

↓↓LDL must be due to LDL-R activityLDL must be due to LDL-R activity

↑↑LDL in homozygous FH probably due to LDL in homozygous FH probably due to lack of uptake of VLDL by liver; transfer to lack of uptake of VLDL by liver; transfer to LDL by lipoprotein lipase, NOT to ↑ apo-B LDL by lipoprotein lipase, NOT to ↑ apo-B synthesis in liversynthesis in liver

A very significant decrease in plasma A very significant decrease in plasma [VLDL] – why?[VLDL] – why?

Two theories, neither satisfactoryTwo theories, neither satisfactory

Theory 1Theory 1: partial inhibition of cholesterol : partial inhibition of cholesterol synthesis means less VLDLsynthesis means less VLDL– Problem: rate of formation of LDL was not reduced; Problem: rate of formation of LDL was not reduced;

this is not the mechanism of action of lovastatinthis is not the mechanism of action of lovastatin

Theory 2Theory 2: Small residue of LDL-R activity : Small residue of LDL-R activity removes remnants, but not LDLremoves remnants, but not LDL– Problem: they’ve established these patients have Problem: they’ve established these patients have

essential NO receptor activity and their experiment is essential NO receptor activity and their experiment is based on a lack of receptor activitybased on a lack of receptor activity

Who approved this IRB?Who approved this IRB?

Is this the best way to answer Is this the best way to answer their question?their question?

Points to considerPoints to consider

Isn’t an animal receptor KO model essentially the same as the Isn’t an animal receptor KO model essentially the same as the human homozygous FH model? Has this experiment already been human homozygous FH model? Has this experiment already been done?done?Is it appropriate to use human subjects to confirm a drug does NOT Is it appropriate to use human subjects to confirm a drug does NOT work?work?– What if you take them off their current treatment for months?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 you feed them a diet that further complicates their illness?– What if they are six-year-old children?What if they are six-year-old children?– What if previous studies seem to indicate that the drug will not work?What if previous studies seem to indicate that the drug will not work?– What if you will be using radioactive iodine isotopes? (invasiveness of What if you will be using radioactive iodine isotopes? (invasiveness of

study)study)How would you pitch this study to a family? (i.e., this probably won’t How would you pitch this study to a family? (i.e., this probably won’t work, but what’s important is why?)work, but what’s important is why?)Is obtaining consent from a 6-yr-old feasible?Is obtaining consent from a 6-yr-old feasible?Does the prognosis of the patients make a difference?Does the prognosis of the patients make a difference?