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EAS 2018 - Breaking News on Lipoprotein(a)

Monday 7 May 2018   (1 Comments)
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How much should lipoprotein(a) be lowered for clinically relevant benefit?

That was the question posed at the First Late Breaking News Session today. Researchers led by Professor Brian A. Ference (Director of Research in Translational Therapeutics, the University of Cambridge, and Benjamin Meaker Visiting Professor, the University of Bristol, UK) provided important insights. These findings are highly pertinent given that phase three trials testing novel agents that have been shown to lower lipoprotein(a) by up to 90% by inhibiting apolipoprotein(a) synthesis are imminent.1

There is strong evidence from observational and genetic studies that lipoprotein(a) is causally associated with coronary heart disease (CHD) risk.2 This evidence supported recommendations made by the EAS Consensus Panel for screening for elevated lipoprotein(a) in individuals at intermediate, high, or very high cardiovascular risk, and desirable levels for this lipoprotein, which have been adopted by European guidelines.3,4 Yet, so far we lack evidence from clinical trials that therapeutic targeting of lipoprotein(a) reduces CHD risk. These previous trials were not, however, specifically aimed at testing the effect of lowering lipoprotein(a). Despite this, the question of how much lipoprotein(a) would need to be lowered to achieve a clinically meaningful effect warrants consideration.

This was addressed in this analysis of five Mendelian randomization studies including data from 48,333 individuals of European descent (20,793 CHD cases). A genetic risk score based on 43 genetic variants of LPA, the gene encoding apolipoprotein(a), a determinant of lipoprotein(a) levels, was used to evaluate the predicted effect of lowering lipoprotein(a) on CHD risk. This genetic score explained up to 63% of the variance in lipoprotein(a) concentration, lower than observed previously, as the score was constructed to minimize bias.5 The results were then validated using summarized data from 48 studies (62,240 CHD cases and 127,299 controls). This approach has been used in previous studies which have accurately predicted the results of recent landmark randomized trials, such as the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) and REVEAL (Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification) trials.6,7

The analysis showed that CHD risk was directly proportional to the absolute change in plasma lipoprotein(a) mass concentration. For each 10 mg/dL lower genetically estimated lipoprotein(a) levels, predicted by the LPA genetic risk score, there was a 5.8% lower CHD risk (95% confidence interval 4.9% to 6.7%). For comparison, each 10 mg/dL lower LDL cholesterol value predicted using an LDL genetic score was associated with a 14.5% lower CHD risk (95% confidence interval 10.7% to 18.2%).  This suggests that 1 mg/dL difference in LDL cholesterol has the same effect on CHD risk as a 2.63 mg/dL difference in lipoprotein(a) concentration.

In other words, a 1 mmol/L (38.7 mg/dL) difference in LDL cholesterol has the same effect as about 100 mg/dL difference in lipoprotein(a).

It is important to bear in mind that these changes in both LDL cholesterol and lipoprotein(a) relate to lifelong exposure to these lipoproteins. Further analyses showed that the expected clinical benefit in CHD risk from both life-long and short-term exposure to absolute differences in lipoprotein(a) concentration were equivalent.

Thus, when considering the design of future trials with potent lipoprotein(a) lowering agents, the findings of this analysis indicate that at least 100 mg/dl reduction in lipoprotein(a) is needed to achieve a about 20% reduction in CHD risk in short-term (3-5 years duration) clinical trials, in line with the benefit observed per mmol/l reduction in LDL cholesterol.  This implies that individuals recruited to such trials should have very high lipoprotein(a) levels at baseline, in the region of about 100 mg/dL or higher. However, as Professor Ference explained, it should not be inferred that individuals with lower lipoprotein(a) levels will not obtain clinical benefit from lipoprotein(a) lowering; they will do although the magnitude of benefit is less.

In discussion, a couple of points were raised. First, Professor John Chapman (Paris, France) noted that apolipoprotein(a) genotype is the main determinant of plasma concentrations of lipoprotein(a), suggesting the need to stratify by apolipoprotein(a) size of variants.  Additionally, Dr. Pia Kamstrup (Copenhagen University Hospital, Denmark) noted that the lipoprotein(a) assay is not uniformly calibrated, and that standardization of results across assays may be indicated, although Professor Ference indicated that the change in lipoprotein(a) concentration across the assays was consistent.

In closing, Professor Ference noted that elevated lipoprotein(a) concentration is mainly inherited. When considering the implications from this analysis, it is clear that individuals with very high lipoprotein(a) levels (greater than 200 mg/dl) are likely to have the same lifetime risk of CHD as in those with heterozygous familial hypercholesterolaemia (FH). Heterozgyous FH is thought to have a prevalence of 1:220-250 in North European populations.8 In contrast, the prevalence of very high lipoprotein(a) levels is thought to be about two-fold higher.9 These findings provide a rationale for a call to action to address this urgent clinical need for diagnosis and treatment of individuals with very high lipoprotein(a) levels.

References

1. Viney NJ, van Capelleveen JC, Geary RS, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 2016;388:2239-2253.

2. Nordestgaard BG, Langsted A. Lipoprotein(a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology. J Lipid Res 2016;57:1953-1975.

3. Nordestgaard BG, Chapman MJ Ray K, Borén J, Andreotti F, Watts GF, Ginsberg H, Amarenco P, Catapano A, Descamps OS, Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Reiner Z, Taskinen MR, Tokgözoglu L, Tybjærg-Hansen A; European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31: 2844–2853.

4. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, Hoes AW, Jennings CS, Landmesser U, Pedersen TR, Reiner Ž, Riccardi G, Taskinen MR, Tokgozoglu L, Verschuren WMM, Vlachopoulos C, Wood DA, Zamorano JL, Cooney MT; ESC Scientific Document Group.. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis 2016;253:281-344.

5. Boerwinkle E, Leffert CC, Lin J, Lackner C, Chiesa G, Hobbs HH. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J Clin Invest 1992; 90:52-60.

6. Ference BA, Robinson JG, Brook RD, Catapano AL, Chapman MJ, Neff DR, Voros S, Giugliano RP, Davey Smith G, Fazio S, Sabatine MS.. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med 2016; 375:2144-2153.

7. Ference BA, Kastelein JJP, Ginsberg HN, Chapman MJ, Nicholls SJ, Ray KK, Packard CJ, Laufs U, Brook RD, Oliver-Williams C, Butterworth AS, Danesh J, Smith GD, Catapano AL, Sabatine MS. Association of genetic variants related to CETP inhibitors and statins with lipoprotein levels and cardiovascular risk.  JAMA 2017; 318:947-956.

8. Benn M, Watts GF, Tybjærg-Hansen A, Nordestgaard BG. Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217. Eur Heart J 2016;37:1384-1394.

9. Varvel S, McConnell JP, Tsimikas S. Prevalence of elevated Lp(a) mass levels and patient thresholds in 532 359 patients in the United States. Arterioscler Thromb Vasc Biol 2016; 36:2239-2245.

 

 

Comments...

Gert Kostner says...
Posted Wednesday 9 May 2018
The suggestion that 38.7 mg/d/L difference in LDL-C might have the same effect as 100 mg/dl of Lp(a) is certainly an average estimate and does not apply for individual patients. It should also be mentioned that 100 mg/dl Lp(a) correspond to roughly 38.5 mg/dl of Lp(a)-C and thus the effect of lowering Lp(a) in mass units of cholesterol is equal tot hat of LDL applying the data from the study of Bryan. Concerning lack of standardized of Lp(a) assays there is currently a very active IFCC working group installed under the guidance of Christa by Cobbaert http://www.ifcc.org/ifcc-scientific-division/sd-working-groups/wg-apo-ms/ aiming to standardize apo-lipoprotein measurements and in particular Lp(a) assays. Hopefully this group will succeed to solve this problem in due time. Karam Kostner and Gert Kostner

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