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Patients with high genetic risk for CHD benefit most from statin therapy
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Adults with the highest genetic risk for CHD derived the greatest benefits from statin therapy, regardless of traditional risk factors, according to new findings.
Researchers analyzed whether a genetic risk score consisting of a composite of variants with known associations with CHD risk could determine future CHD events and identify the individuals who could benefit most from statin therapy.
Jessica L. Mega
Jessica L. Mega, MD, MPH, from the TIMI Study Group of the cardiovascular division at Brigham and Women’s Hospital and Harvard Medical School, and colleagues conducted an analysis of 48,421 adults from five studies: the Malmo Diet and Cancer Study, a community-based cohort study; the JUPITER and ASCOT randomized controlled trials of statin therapy for primary prevention; and the CARE and PROVE IT-TIMI 22 randomized controlled trials of statin therapy for secondary prevention. In total, 3,477 CHD events were documented.
Mega and colleagues investigated the association between the genetic risk score based on 27 variants and incident or recurrent CHD, adjusting for traditional clinical risk factors. Participants were stratified into quintiles based on genetic risk. The researchers assessed the absolute and relative risk reductions in CHD with statin therapy stratified by genetic risk.
Genetic risk score tracked with CHD risk
Compared with the quintile of lowest genetic risk, individuals in the three quintiles of intermediate genetic risk (HR = 1.34; 95% CI, 1.22-1.47) and those in the quintile with the highest genetic risk (HR = 1.72; 95% CI, 1.55-1.92) had an elevated risk for CHD.
In the four randomized trials of statin therapy, the researchers observed a significant gradient of increasing relative risk reductions across the low (13%), intermediate (29%) and high (48%) genetic risk categories associated with statin therapy (P = .0277).
Individuals in higher risk categories had greater absolute risk reductions compared with individuals in lower risk categories (P = .0101).
This corresponded to an approximately threefold decrease in the number needed to treat to prevent one CHD event in the primary prevention trials, the researchers wrote. The number needed to treat to prevent one CHD event in 10 years was 66 individuals of low genetic risk, 42 of intermediate genetic risk and 25 of high genetic risk in JUPITER and 57 of low genetic risk, 47 of intermediate genetic risk and 20 of high genetic risk in ASCOT.
Patient identification
“We can at least say that patients with a high genetic risk score appear to benefit more from statin therapy because they’re starting at a higher baseline risk, even controlling for all the clinical measures we routinely examine,” investigator Nathan O. Stitziel, MD, from the cardiovascular division of the department of medicine and the division of statistical genomics at Washington University School of Medicine, St. Louis, said in a press release. “The panel of genetic markers we analyzed provide a way to identify the patients starting out at higher baseline risk. This is important because it appears to be independent of cholesterol levels and other traditional markers of heart disease that we typically use to estimate risk.” – by Erik Swain
Disclosures: The present study was supported by the NHLBI. JUPITER was supported by AstraZeneca, ASCOT was supported by Pfizer, CARE was supported by Bristol-Myers Squibb, PROVE IT-TIMI 22 was supported by Bristol-Myers Squibb and Sankyo, and the Malmo Diet and Cancer Study was supported in part by the Novo Nordisk Foundation. Mega reports financial ties with American Genomics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Bristol-Myers Squibb/Sanofi, Daiichi Sankyo, Janssen Pharmaceuticals and Sankyo. Stitziel reports receiving personal fees from American Genomics.
Perspective
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Robert Roberts, MD, FRSC, FRCPC, MACC, LLD (Hon.)
This is the first report of the application of genetic risk to be shown to be associated with improved therapeutic outcomes. This is a very promising report.
The findings have the potential to change the considerations doctors make when trying to prevent CHD in their patients. If you have an LDL of 130 mg/dL and no other risk factors, you don’t need to treat it. What this clearly indicates is if that you assess risk via the 27 single nucleotide polymorphisms, and you divide people into high, intermediate and low risk, now you have an independent risk factor in those at high or intermediate risk, and those would be treated in the near future where they wouldn’t be otherwise.
Also, there is debate about whether people who have minimally or moderately elevated LDL without risk factors should be treated at all, since there are some concerns about side effects of statins. This genetic risk factor today, at whatever level your cholesterol is, can be utilized to separate you into high or low risk. In certain individuals — particularly those more prone to diabetes, because statins have the potential to increase the odds of developing diabetes — that you would now have a choice whether to treat them with statins or not, and perhaps only treat those at high risk based on the genetic risk score.
People who are more at risk for the side effects of statins could now be evaluated with this risk score and those at low risk can feel more comfortable with not taking statins, while those at high risk, if they don’t want to take a statin, probably should take another cholesterol-lowering agent, whether it is a fibrate or a resin or ezetimibe (Zetia, Merck).
I don’t know whether a change in practice will happen right now. Having a genetic risk factor test performed is pretty easy today. The technology is there. I think what will delay it coming into practice is that this is the first study; it is retrospective and involved a heterogeneous group from different trials. This will certainly have to be repeated, preferably as a prospective study, before it is going to be considered as part of the guidelines in clinical practice. One would compare prospectively in an independent population those based on traditional risk factors vs. those based on traditional risk factors plus genetics, and look at outcomes.
It is very important now for the community to realize that while we have always known that 40% to 60% of our risk for CVD is genetic, we have now identified many genetic risk factors. The authors of the present study used 27. There are now about 50 genetic risk factors that have been identified, published and verified (Roberts R. Circulation Research. 2014;doi:10.1161/CIRCRESAHA.114.302692), and more that will be published soon. The next study should be prospective and include as many risk factors as are available, which will only improve one’s ability to stratify into high and low risk.
For personalized medicine, this is a step forward in the right direction. We were limited until 2007, when the first genetic risk factor, 9P21, was discovered. Now that we have all of these genetic risk factors, and this report showing that the potential is very high to personalize therapy on the basis of a genetic score, this is a true beginning for management of CAD.
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