Pharmacogenomics of Statins- Follen

Statins are what type of inhibitors?

HMG-CoA Reductase Inhibitors

Statins are used for primary and secondary prevention of __________________________.

Cardiovascular events

What are the risk factors for statin-related myopathy?

• older age

• low BMI

• asian/african

• hepatic/renal disease

• diabetes, hypothyroidism

• excessive alcohol consumption

• intense physical exercise

• high dose statin

• drug-drug interactions

With what haplotypes of the SLCO1B1 gene is there an increased risk of Simvastatin myopathy?

SATA:

a. *5

b. *10

c. *15

d. *17

a, c, d

In SLCO1B1 gene polymorphism, the T nucleotide is subbed with a _____.

a. U

b. G

c. C

d. A

c- C nucleotide

With what statin is there the most evidence regarding SLCO1B1?

a. Atorvastatin

b. Simvastatin

c. Rosuvastatin

d. Pravastatin

b. Simvastatin

The SLCO1B1 gene codes for the production of what protein?

OATP1B1

The OATP1B1 protein does what function?

is involved in hepatocyte uptake of statins

In pts. with the 521C polymorphism in the SLCO1B1 gene, how does that effect the function of the OATP1B1 protein? What is the result of this effect?

decreases activity

• therefore, statin can’t get in the liver, increase statin conc in plasma

In the end, pts. with the 521C polymorphism in the SLCO1B1 gene, have an increased risk of what side effect?

MYOPATHY

Summary of how SLCO1B1 gene polymorphism 512C effects OATP1B1:

• basically if you got the 521C gene instead of 521T gene, you have increased risk of myopathy

  • this is seen with any haplotype of the 521C gene as well (*5,*15,*17)

If 1a, 1b are considered normal genes, and *5, *15, *15 are considered mutant genes,

A normal patient could have which possible gene combos?

1a/1a

1a/1b

1b/1b

If 1a, 1b are considered normal genes, and *5, *15, *17 are considered mutant genes, A heterozygous pt could have what possible gene combos?

they have one normal gene (1a,1b), and one mutant gene (*5,*15,*17)

1a/*5 or *15 or *17

• ex: 1a/*15

1b/*5 or *15 or *17

• ex: 1b/*17

What genotypes (TT,TC, CC) are assigned to each SLCO1B1 genetic variants?

Normal-

Heterozygous-

Mutant-

Normal- TT

Heterozygous- TC

Mutant- CC

How would the OAT protein activity of a heterozygous pt (one normal, one mutant) be?

• you would see intermediate activity of OAT bc only one mutant gene

If 1a, 1b are considered normal genes, and *5, *15, *15 are considered mutant genes, a person with low activity of OAT protein would have which gene combos?

two mutant genes!!!

Ex: *5/*5 , *5/*15, *15/*17 (many combos)

Just because someone has normal OATP1B1 protein function, does that mean they have 0% risk of myopathy?

no

If a patient is TC, or CC for the SLCO1B1 gene, what is the recommended dosing of Simvastatin?

• lower the dose

• consider alternative statin

• monitor CK

If a patient is TT for the SLCO1B1 gene, what is the recommended dosing of Simvastatin?

• prescribe normal starting dose

• or adjust based on specific diseases

*5 is shown to increase risk of simvastatin associated myopathy in patients who also have low _____________________________.

low serum vitamin D3

Supplementing ___________ with Simvastatin can reduce myalgia and muscle related ADRs.

CoQ10

Do lipophilic or hydrophilic statins have a higher risk of myopathy?

lipophilic

What are the names of the hydrophilic statins that lower risk of myopathy?

• Pravastatin

• Rosuvastatin

With Simvastatin what are some CYP3A4 interactions? (Classify them by strong, moderate, or other)

Strong

• gemfibrozil

Moderate

• non-DHPs

• dronedarone

Other

• amiodarone

• amlodipine

• ranolazine

How do we adjust the dose of Simvastatin based on strong, moderate, or other inhibitors of CYP3A4?

strong- contraindicated

moderate- 10mg/day

other- 20mg/day