MedicalResearch.com Interview with:
Dr. Stephen Burgess PhD
Programme Leader at the Medical Research Council Biostatistics Unit
University of Cambridge
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Lipoprotein(a) is a lipoprotein subclass, and an important biomarker for coronary heart disease. As a clinical biomarker, it has a similar story to LDL-cholesterol (“bad” cholesterol), in that it is thought to be a causal risk factor for coronary heart disease, and so is a potential target for drug development. However, while drugs that lower LDL-cholesterol, such as statins, have been successful in reducing coronary heart disease risk, drugs that lower lipoprotein(a) have not as yet been successful. New drugs are currently in development that specifically target lipoprotein(a) and can lower lipoprotein(a) concentrations by 80-90%. We performed this study to investigate whether these drugs are likely to be successful in reducing coronary heart disease risk.
We compared individuals with naturally-occurring genetic variants that predispose them to a higher or lower lifetime concentration of lipoprotein(a) as a way of mimicking a randomized controlled trial. This approach has previously been undertaken for other biomarkers, including LDL-cholesterol. We found that having 10mg/dL lower genetically-predicted concentration of lipoprotein(a) was associated with a 5.8% reduction in coronary heart disease risk.
However, associations between genetically-predicted LDL-cholesterol and coronary heart disease risk are quantitatively much stronger than the proportional effect of LDL-cholesterol lowering on coronary heart disease risk as estimated by statin trials. This is because differences in genetic variants reflect lifelong changes in LDL-cholesterol, whereas statin trials only lower LDL-cholesterol for a few years. Hence, using the ratio between the genetic and trial estimates for LDL-cholesterol, we estimate that lowering lipoprotein(a) by 10mg/dL in a short-term clinical trial would only reduce coronary heart disease risk by 2.7%. To obtain the same reduction in coronary heart disease risk of around 20% as observed in statin trials, lipoprotein(a) would have to be lowered by around 100mg/dL. This explains why previous trials of less specific and less potent lipoprotein(a)-lowering drugs have failed to demonstrate benefit.
MedicalResearch.com: What should clinicians and patients take away from your report?
Response: While lipoprotein(a) is likely to be a causal risk factor for coronary heart disease, and so a valid drug target, lipoprotein(a) levels need to be reduced substantially for there to be measurable clinical benefit. As the median concentration of lipoprotein(a) in European-descent populations is around 10-20 mg/dL or lower, even the most potent lipoprotein(a)-lowering drugs will have limited benefit. Only around 1% to 4% of European-descent individuals have a lipoprotein(a) concentration above 100mg/dL, although this number is larger in some other ethnic groups.
On a more optimistic note, the benefit of lifetime lipoprotein(a) lowering is more substantial. Individuals with very high levels of lipoprotein(a) have a similar lifetime coronary heart disease risk as individuals with heterozygous familial hypercholesterolemia, but are around twice as prevalent in the population. Identifying such individuals by genetic or phenotypic screening and lowering their lipoprotein(a) concentrations across the lifecourse could have considerable impact for reducing the global burden of coronary heart disease.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: This investigation has important implications for trials of lipoprotein(a) concentrations. Unless these specifically target individuals with elevated lipoprotein(a) concentrations, the trials will not demonstrate clinical benefit. It also has implications for patients, suggesting lipoprotein(a) lowering therapies will be a “precision medicine”, which should be targeted appropriately. Finally, it has implications for individuals with high cholesterol measurements who do not respond to statin and other conventional lipid-lowering medicines – it may be that these cholesterol measurements reflect high lipoprotein(a) concentrations, and so should be treated with lipoprotein(a)-lowering agents.
Disclosures: This work was supported by the Wellcome Trust, the Royal Society, the UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Commission, and the European Research Council.
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Burgess S, Ference BA, Staley JR, et al. Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies A Mendelian Randomization Analysis. JAMA Cardiol.Published online June 20, 2018. doi:10.1001/jamacardio.2018.1470
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