Gene testing could find those who would benefit most from statins

“Patients with the highest genetic risk of suffering a heart attack benefit the most from cholesterol-lowering statin drugs,” The Guardian reports.

Statins are drugs that lower cholesterol and can help reduce the risk of coronary heart disease (CHD) developing – the leading cause of death both in the UK and worldwide.

Researchers studied genetic risk factors previously discovered for CHD in 48,421 adults, and used them to group people into low, intermediate and high risk categories. They next looked at the effect of statins on reducing new and recurring CHD “events” such as heart attacks. Compared with not taking them, statins reduced CHD events by 13% in the low-risk group, 29% in the intermediate group and 48% in the high-risk group.

Current UK recommendations are that people should be offered statins if there is at least a one in 10 chance of them developing CHD at some point in the next 10 years.

Critics of these recommendations argue that this means they are given to people who don’t really need them, which could waste money and subject people unnecessarily to the possible side effects of statins.

The work carried out in this study could improve the ability to assess who is at high risk.

The findings need to be confirmed by other research, but suggest that genetic risk factor categories could be used, alongside other risk factors, to identify groups who may benefit most from statins.

Where did the story come from?

The study was carried out by academic and medical research institutions in the US and Sweden, and was funded by the National Institutes of Health and a large number of public and private sources. The study used data from existing trials that were supported by drugs companies, as well as public research councils. 

Many of the authors have received funding, such as research grants, from drugs companies. Due to the nature of the research, this is not surprising. A study of this size and scale, involving so many researchers, would be near-impossible to carry out without any industry involvement. 

A detailed list of these declarations of interest was given in the publication. The publication stated: “For this analysis, the funders of the individual clinical trials had no role in the analysis or interpretation of the data, or writing of the report.”

The study was published in the peer-reviewed medical journal The Lancet.

Generally, The Guardian reported the story accurately, but linked the risk reduction figures solely to heart attacks. The figures actually referred to a mixed group of CHD events. Most of them were fatal or non-fatal heart attacks, but it also included some cases of unstable angina, heart bypasses, or other heart interventions. This isn’t a big issue, but something to be aware of.

What kind of research was this?

This was a mixed method study looking at whether genetic risk factors can predict CHD, and if these might be used to identify people who would get the most benefit from using statins.

CHD is the leading cause of death both in the UK and worldwide.

It’s responsible for around 73,000 deaths in the UK each year. About one in six men and one in 10 women die from CHD.

In the UK, there are an estimated 2.3 million people living with the condition and around 2 million people affected by angina – the most common symptom of CHD. Read more about the symptoms of CHD.

Genetic variations in DNA have been linked to higher risk of CHD in previous research. In this new study, they tested whether or not a combination of these variants could predict the risk of new or recurrent CHD events, and whether this could identify people who get the most benefit from statin therapy.

What did the research involve?

The researchers analysed data from four randomised controlled trials (RCTs) and one cohort study, to look at the link between genetic risk factors and CHD events. They then looked at the relative risk and absolute risk reductions in CHD through using statins, stratified across the different genetic risk groups.

The studies included were a Swedish community-based cohort study (the Malmo Diet and Cancer Study) and four RCTs. Two of the RCTs looked at the ability of statins or anti-hypertension medication to prevent cardiovascular disease (CVD) compared with placebo (JUPITER and ASCOT). The other two recruited people with a history of CVD and assessed statin therapy to prevent recurrences (CARE and PROVE IT-TIMI 22).

The researchers studied the association of a genetic risk score based on 27 genetic variants with new or recurrent CHD, which had been identified in previous studies. Risk scores were used to group people into low, intermediate and high-risk categories.

This provided results for 48,421 individuals, with 3,477 CHD events for the final analyses.

Results were pooled in a meta-analysis, which adjusted for traditional CHD risk factors:

• age
• sex
• diabetes status
• smoking
• race (if applicable)
• family history of coronary heart disease
• HDL cholesterol
• LDL cholesterol
• hypertension

Definitions of CHD differed across the studies, so they used CHD events as the main outcome.

This covered:

• fatal or non-fatal heart attack
• death due to CHD
• unstable angina
• coronary artery bypass grafting – when blood is diverted past a blockage in the artery
• coronary angioplasty – when a blocked artery is widened

What were the basic results?

Higher genetic risk scores were associated with a higher risk of CHD, independent of the known risk factors.

The main findings combined all four studies and outcomes for new and recurring CHD events. Compared with the lowest-risk group, those in the intermediate-risk category were 34% more likely to have a CHD event (hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.22 to 1.47). Those in the high-risk group were 73% more likely (HR 1.72, 95% CI 1.55 to 1.92) to have a CHD event.

This was confirmation that the genetic grouping was potentially useful in signalling the risk of a CHD event.

The next results were on how effective statins were across the genetic risk groups. Compared with not taking them, statins reduced CHD events by 13% in the low-risk group, 29% in the intermediate group and 48% in the high-risk group.

Focussing on the JUPITER primary prevention trial, the number of people needed to take statins to prevent one CHD event in 10 years was 66 in the low-risk group, 42 for intermediate risk and 25 for the highest-risk.

The corresponding figures in the ASCOT cohort were 57 low, 47 intermediate and 20 high.

Across all four studies, there were statistically significant reductions in relative and absolute risk reduction using statins, with higher-risk groups benefiting more.

How did the researchers interpret the results?

The authors said: “When combined into a 27-variant risk score, our multivariable-adjusted analyses showed that these variants could identify people at increased risk of CHD events, including incident CHD in primary prevention populations and recurrent CHD events in secondary prevention populations.

“Furthermore, when compared with people at low genetic risk, those with the highest genetic risk scores derived greater relative risk reduction and absolute risk reduction with statin therapy. Notably, in the primary prevention trials, we found a roughly threefold difference between the low and high genetic risk score groups in the number needed to treat to prevent one CHD event.

Dr Nathan Stitziel, from Washington University, in the US, who co-led the research, was quoted in the Guardian as saying: “We need more research to confirm these results. Regardless, we can 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.”

Conclusion

This study showed how a genetic risk factor score can categorise people into groups at low, intermediate and high risk of having a CHD event, like a heart attack. They found that statins helped all the groups reduce their risk of a CHD event, but helped those with the higher risks more.

The genetic risk categories were tested in over 48,000 people, but the authors themselves acknowledge that more research is needed to confirm the findings.

That withstanding, this type of research has potentially interesting implications. It may, for example, help us to understand how different groups may or may not benefit from statins, and attempt to quantify this benefit. This has the potential to help optimise statin prescriptions, taking into account genetic factors, as well as other risk factors used now, like age, diabetes status, smoking, cholesterol levels and high blood pressure.

Knowing about genetic risk factors may not be necessary in all decisions regarding statins, but might help in some.

A final factor not discussed in the study is the issue of cost. Genetic sequencing is a lot cheaper than it was a decade ago, and costs are expected to continue to fall, but it may not be cost-effective to run gene tests on large sections of the population.

You can always reduce your need to take statins and reduce your risk of a CHD event by stopping smoking, eating healthily, being physically active, and keeping your blood pressure and cholesterol within normal limits.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

Links To The Headlines

Statins work for those at highest risk of heart attack – study. The Guardian, February March 4 2015

Links To Science

Mega JL, Stitzel NO, Smith JG, et al. Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials. The Lancet. Published online March 4 2015