Genetically Guided Statin Therapy

HMG Co-A reductase inhibitors ("statins") are commonly prescribed to lower low density
lipoprotein cholesterol (LDLc) and to prevent cardiovascular disease (CVD), a leading cause
of morbidity and mortality. Long-term adherence to statins in the primary care environment
is challenging; consequences of statin non-adherence include higher LDLc levels,
hospitalizations, costs, and death due to CVD.

Medication non-adherence is complex and multifactorial and can be associated with a number
of factors including medication cost, complexity of medication regimen, poor
provider-patient relationship / communication, and adverse side effects. For statins, side
effects such as muscle aches, cramping, and pain (referred to broadly as statin-related
myopathy) are a frequent cause of non-adherence. These symptoms are non-specific and are
frequent reasons for stopping statin therapy, due to patient or provider concern about the
possibility of statin-related myopathy. Many patients may be needlessly deprived of the
cardiovascular benefits of long-term statin use.

A genetic risk factor for statin myopathy and subsequent non-adherence has recently been
identified. In a genome-wide association study, a genetic variant (named SLCO1B1*5) was a
main contributor of statin myopathy. It was demonstrated that the SLCO1B1*5 variant is not
only a predictor of myopathy, but also of premature statin discontinuation. The risk with
the *5 allele is statin specific: greatest with simvastatin and atorvastatin use, the least
with pravastatin or rosuvastatin. Therefore, the SLCO1B1*5 variant is common, can predict
myopathy, subsequent non-adherence, and due to its statin-specific effects creates a novel
research paradigm for personalizing statins to an individual's genetic profile. Carriers of
the SLCO1B1*5 variant may do best on rosuvastatin, pravastatin, or fluvastatin whereas
non-carriers may be treated with any statin.

The objective of this study is to conduct a randomized trial comparing two strategies:

1. genetically guided statin therapy vs.

2. usual care (i.e., a strategy without genetics) on the effects of statin adherence and
LDLc lowering.

The overall hypothesis is that genetically guided statin therapy will lead to greater statin
adherence and lower LDLc when compared to a non-guided strategy. The design of this trial
will randomize primary care patients within Duke University Health System (DUHS) and travis
Air Force Base (TAFB) clinics that are nonadherent to statins due to prior side-effects in
an unblinded, 1:1 fashion, stratified by SLCO1B1*5 genotype.

Inclusion Criteria:

- Current patient (defined as seen in the last year) of the Duke Primary Care at
Pickett Road, Pickens Family Medicine Center or Travis AFB

- Age greater than or equal to 18 years

- Current non-utilization of statin therapy for either of the following reasons: (a)
Prior side effects thought to be attributed by the patient to statin use AND/OR (b)
Physician removal of statin due to presumed associated side effects

- No statin use for the past 6 weeks

- Active email account

- Computer access available in order to complete on-line surveys

- Ability to provide informed consent

Exclusion Criteria:

- Prior rhabdomyolysis, or CK elevation > 10 times the upper limit of normal with any
statin therapy

- Prior unexplained elevation in hepatic enzymes (AST or ALT > 3 times upper limit of
normal) with any statin therapy

- Current daily grapefruit juice usage (on average >1quart/day)

- Expected long term use (longer than 3 months) of the following medications known to
interfere with statin metabolism or disposition at time of enrollment until the
randomization is complete. However, short-term (<14 days) is allowed for the duration
of the study

- Participation in a drug research study in the past 30 days

- Previous use of 4 or more statins