"Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies: A Mendelian randomization analysis" out today at JAMA Cardiology ja.ma/2K52Pf7. Tweetorial follows!
Lipoprotein(a) is an important biomarker for coronary heart disease, and a potential target for drug development. New drugs in development can lower lipoprotein(a) concentrations by 80-90%. We investigated whether these drugs are likely to reduce coronary heart disease risk.
We compared individuals with naturally-occurring genetic variants that predispose them to a higher or lower lifetime concentration of Lp(a) as a way of mimicking a randomized controlled trial. This approach has previously been undertaken for biomarkers such as 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 CHD risk are quantitatively much stronger than the 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.
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.
Unless future trials of lipoprotein(a) lower specifically target individuals with elevated lipoprotein(a) concentrations, the trials will not demonstrate clinical benefit.
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 for individuals with average lipoprotein(a) levels.
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 CHD risk as those with heterozygous FH
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.
This 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.
In short, our study suggests that lipoprotein(a) lowering therapies will reduce coronary heart disease risk, but the expected benefit will be marginal in individuals with average levels of lipoprotein(a).
Substantial risk reduction - similar in magnitude to that observed for statins - is achievable, but amongst individuals of European ancestry only for those in the top percentiles of the lipoprotein(a) distribution. FIN
