Personalized Cardiology - Applications of Biotechnology in Cardiovascular Therapeutics - page 330

The STRENGTH Study
The STRENGTH study (Statin Response Examined by Genetic HAP Markers) was
launched in 2001 by Genaissance Inc (acquired by Clinical Data Inc). It is the larg-
est prospective clinical trial ever conducted to discover how physicians can person-
alize prescriptions using information about human genomic variation. As the
earliest application of pharmacogenomics to one of the most prevalent public health
problems − hypercholesterolemia − the study is designed to provide the information
necessary for physicians to decide which cholesterol lowering drug is best for each
patient based on their own genetic makeup. The four drugs under study were:
Lipitor (atorvastatin), Zocor (simvastatin), Pravachol (pravastatin), and Baycol
(cerivastatin). In 2002, new results were announced from ongoing analyses of the
STRENGTH I clinical study that further demonstrate the ability of its HAP
Technology to identify specific genetic markers (gene haplotypes or HAP Markers)
that are associated with the effects of statin therapy, including LDL (bad) choles-
terol, HDL (good) cholesterol, and triglycerides.
The study has examined 100 genes so far from three functional pathways (lipid
metabolism and transport, inflammation, and drug metabolism). A total of 29 HAP
Markers from 27 of these genes were found to have statistically significant associa-
tions with clinical response (LDL, HDL, and/or triglycerides) to simvastatin, ator-
vastatin, or pravastatin. Each HAP Marker occurred in at least 10% of the study
group and, thus, may have wide clinical applicability across the population of
patients with hyperlipidemia. Twenty-five of the markers were linked to outcomes
for specific drugs and four were associated with the effects of statins as a drug class.
These important findings highlight the differences between drugs in the statin class
and clearly indicate the need and the potential to optimize therapy based on the
genetics of different patient populations. The medical community has been aware
of clinical and metabolic differences among the statins but this study provided some
genetic evidence that begins to explain these differential effects.
Two examples of drug-specific markers are based on a deeper analysis that was
completed for 25 genes. A marker from one gene was associated with a positive
HDL cholesterol clinical response in one of the statins, a negative response in a
second drug and no change in HDL response in a third. It is notable that the same
marker predicts opposing effects for two of the drugs. This marker, found in 26% of
the STRENGTH patients, illustrates how differently the drugs interact with biologi-
cal pathways and may help to explain the variation in the HDL response of patients
when taking different statins. In this study, this one predictive marker is as powerful
as all of the other currently available predictors put together, including age, alcohol
use, smoking, gender, body mass index, exercise, and baseline HDL levels. Further
analyses of STRENGTH data include the evaluation of additional markers for drug
efficacy as well as markers that may be predictive of side effects, such as muscle
damage. Further clinical studies have continued on this topic (Jain 2011 ).
Marked lowering of low-density-lipoprotein cholesterol (LDL-C) levels (< or =
50%) with intensive statin therapy is associated with major reduction in cardiovas-
cular risk, but is limited by a potential increase in adverse effects, thereby justifying