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Prognostic value of serum lipoprotein(a) levels on long-term mortality in a large sample of subjects in primary cardiovascular prevention: Data from the Brisighella Heart Study
Abstracts / Atherosclerosis 252 (2016) e1ee196
Conclusions: LA can be used safely for pediatric patients with CTE due to elevated Lp(a).
EAS16-0311, LIPOPROTEINS AND LIPID METABOLISM: LP(A). RATIONALE AND DESIGN OF A CLINICAL TRIAL TO ASSESS LP(A) LOWERING WITH IONIS-APO(A)-LRX IN PATIENTS UNDERGOING APHERESIS FOR ELEVATED LP(A) AND RECURRENT CARDIOVASCULAR EVENTS P.M. Moriarty 1, E.S. Thiessen 2, J.L. Witztum 3, N.J. Viney 4, S. Tsimikas 5. 1 University of Kansas Medical Center, Clinical Pharmacology, Kansas City, USA; 2 Charite-Universitaetsm edizin, LIpid Ambulatory Clinic, Berlin, Germany; 3 UCSD, Endocrinology, La Jolla, USA; 4 Ionis Pharmaceuticals, Pharmaceuticals, Carlsbad, USA; 5 USA Objectives: Patients with recurrent major adverse cardiovascular events (MACE), controlled LDL-C but Lp(a) >60 mg/dL are treated with Lipoprotein-Apheresis (LA) in Germany and ad hoc elsewhere. LA results in 60-80% MACE reduction and in 60-80% acute reduction of Lp(a). However, due to rapid liver production the time-averaged Lp(a) reduction is only 30-35%. More potent Lp(a)-lowering agents are needed to prevent MACE in highrisk patients. Methods: IONIS-APO(a)-LRx, an optimized second generation antisense oligonucleotide (ASO) that also contains an N-acetylgalactosamine moiety targeted to the hepatocyte asialoglycoprotein receptor, has a ~32X higher potency compared to the unconjugated ASO. In prior studies, volunteers with Lp(a) >30mg/dL treated with single doses of 10, 20, 40 and 80mg subcutaneously had -26%, -33%, -44% and -79% mean percentage reductions in Lp(a), respectively, and with multiple doses (6 doses over 22 days) of 10, 20 and 40mg had -66%, -82% and -92% reductions, respectively (p0.001 for all). Results: Patients on weekly or bi-weekly LA will be assessed for timeaveraged percent reductions in Lp(a) over a 1-month period. LA will then be replaced by weekly dosing of 30mg IONIS-APO(a)-LRx for 13 weeks and followed for another 16 weeks. The primary endpoint will be the difference in the mean time-averaged reduction in Lp(a) on LA vs. IONIS-APO(a)-LRx. Other endpoints include reduction in oxidized phospholipids on apoB at 13 weeks and time to reinstitution of LA in the follow-up period. Conclusions: IONIS-APO(a)-LRx has the potential to produce greater reductions in Lp(a) and enhance quality of life compared to Lipid Apheresis.
EAS16-0314, LIPOPROTEINS AND LIPID METABOLISM: LP(A). PREVALENCE OF LPA SINGLE NUCLEOTIDE POLYMORPHISMS AND ISOFORMS IN PATIENTS ENROLLED IN A PHASE 2 IONIS-APO(A)RX CLINICAL TRIAL E.S. Stroes 1, F.M. van der Valk 1, D. Gaudet 2, I. Gouni-Berthold 3, N.P. Riksen 4, E. Steinhagen-Thiessen 5, B. Isermann 6, B. Nordestgaard 7, N.J. Viney 8, S. Marcovina 9, S.G. Hughes 8, J. Tami 10, S. Xia 11, J.L. Witztum 12, S. Tsimikas 13. 1 Academic Medical Center- Amsterdam, Medicine, Amsterdam, Netherlands; 2 Universite de Montreal and Ecogene21 Clinical Reserach centre, Medicine, Chicoutimi, Canada; 3 University of Cologne, Medicine, Cologne, Germany; 4 Rabdoud University Medical Centre, Medicine, Nijmegen, Netherlands; 5 Lipid Ambulatory ClinicCharite-Universitaetsm edizin, Medicine, Berlin, Germany; 6 6Institut für klinische chemie und Biochemie- Lipidambulanz- Germany, Medicine, Magdeburg, Germany; 7 Herlev Hospital- Copenhagen University HospitalUniversity of Copenhagen- Denmark, Medicine, Copenhagen, Denmark; 8 Ionis Pharmaceuticals- Carlsbad- CA, Pharmaceuticals, Carlsbad, USA; 9 University of Washington- Seattle- WA, Medicine, Seattle, USA; 10 Ionis Pharmaceuticals, Pharmaceuticals, Carlesbad, USA; 11 Ionis Pharmaceuticals, Pharmaceuticals, Carlsbad, USA; 12 UCSD, Medicine/endocrinology, La Jolla, USA; 13 USA Objectives: Elevated Lp(a) is an independent predictor of CVD and aortic stenosis. Lp(a) levels are genetically determined by apo(a) isoforms, and by single nucleotide polymorphisms (snps) rs10455872 and rs3798220 in European communities (prevalence ~7-15% and ~3%, respectively). The
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distribution in patients eligible for clinical trials of Lp(a) lowering is unknown Methods: A phase 2 study (n¼64) randomizing patients with Lp(a) 125438 nmol/L (~50-175 mg/dL) or 438 nmol/L (~175 mg/dL), representing the 80th and >99th percentile of Lp(a), was conducted with IONISAPO(a)Rx [previously called ISIS-APO(a)Rx], an antisense oligonucleotide to apo(a). The size of the major apo(a) isoform was available in 63 patients and rs3798220 and rs10455872 in 60 patients Results: Patients were recruited from high-risk lipid clinics in Canada and Europe. Average age was 55, 48.4% female, 96.9% white, and 36.9% had history of CVD. Mean (range) LDL-C was 122 (49-238) mg/dL, median (range) Lp(a) was 276 (140-803) nmol/L and mean size (range) of apo(a) isoforms was 16.7 (12-20) KIV repeats. 46/60 (76.7%) of patients had risk alleles of rs3798220 and/or rs10455872: 20 (33.3%) rs3798220 and 18 (30.0%) s10455872 heterozygotes, 4 (6.7%) compound heterozygotes, and 1 (1.7%) s3798220 and 3 (5.0%) rs10455872 homozygotes, respectively. 10/11 (90.9%) patients with Lp(a) 438 nmol/L had snps rs3798220 and/or rs10455872. The highest Lp(a) levels were present in homozygotes/compound heterozygotes or 12-16 KIV repeats Conclusions: Patients with elevated Lp(a) (125 nmol/L or ~50 mg/dL) generally had 20 KIV repeats and were more likely to be carriers of rs10455872 and rs3798220 relative to historical community controls
EAS16-0315, LIPOPROTEINS AND LIPID METABOLISM: LP(A). NATURAL TEMPORAL VARIABILITY IN LP(A) LEVELS IN PATIENTS ENROLLED IN THE PLACEBO ARMS OF IONIS-APO(A)RX ANTISENSE OLIGONUCLEOTIDE CLINICAL TRIALS N.J. Viney 1, S. Marcovina 2, J. Tami 3, S. Xia 3, J.L. Witztum 4, S. Tsimikas 5. 1 Ionis Pharmaceuticals, Pharmaceuticals, Carlsbad, USA; 2 University of Washington- Seattle- WA, Medicine, Seattle, USA; 3 Ionis Pharmaceuticals, Pharmaceutical, Carlsbad, USA; 4 UCSD, Medicine/ endocrinology, La Jolla, USA; 5 USA Objectives: Lp(a) levels are thought to fluctuate minimally, but this is not well studied Methods: The temporal variability in Lp(a) levels was evaluated in placebo groups of IONIS-APO(a)Rx, a generation 2+ ASO : Study 1- in normal volunteers [n¼4 for single ascending dose (SAD) and n¼6 for multiple (MAD) cohorts] with Lp(a) ~25 nmol/L(~10 mg/dL); and Study 2- patients (n¼29) with Lp(a) 125 nmol/L(~50 mg/dL). Serial blood samples (range 7-12) were obtained over 30-190 days. Lp(a) was measured at the Northwest Lipid Metabolism and Diabetes Research Laboratories Results: The median(IQR) baseline Lp(a) was 18 (11, 50) nmol/L for SAD, 166 (101, 205) nmol/L for MAD in Study 1, and 223 (188, 360) nmol/L in Study 2. The greatest variability at any timepoint was -18 to +19 nmol/L for SAD, -93 to +22 nmol/L for MAD in Study 1 and -125 to +101 nmol/L in Study 2, respectively. Evaluated as %D from baseline, variability was -65 to +100% for SAD, -36 to +62% for MAD in Study 1 and -37 to +54 % in Study 2. In study 1, the mean % of timepoints that vary <¼20% were 60% for SAD, 82% for MAD, and in Study 2 89%. There were 3(75%) outliers (defined as >20% difference from baseline at any timepoint) for SAD and 3(50%) for MAD in Study 1, and 14(48%) in Study 2 Conclusions: The natural variability of Lp(a) is more apparent in subjects with low vs. high levels, consistent with a strong genetic influence in plasma levels
EAS16-0330, LIPOPROTEINS AND LIPID METABOLISM: LP(A). PROGNOSTIC VALUE OF SERUM LIPOPROTEIN(A) LEVELS ON LONGTERM MORTALITY IN A LARGE SAMPLE OF SUBJECTS IN PRIMARY CARDIOVASCULAR PREVENTION: DATA FROM THE BRISIGHELLA HEART STUDY F. Fogacci, S. D'Addato, A.F.G. Cicero, E. Bertagnin, S. Palmisano, L. D'Agostini, E. Grandi, M. Giovannini, C. Borghi. Alma Mater Studiorum University of Bologna, Department of Medical and Surgical Sciences, Bologna, Italy
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Abstracts / Atherosclerosis 252 (2016) e1ee196
Objectives: To assess whether serum Lp(a) levels can significantly influence long-term survival in subjects with an equal general cardiovascularrisk-profile. Methods: This study involved a Brisighella Heart Study cohort sample of 1172 adult subjects (M:573;F:599; aged 40-69) with no cardiovasculardiseases at enrollment. According to the CUORE project risk-charts (Italianspecific risk-charts), individuals were stratified into low-(n¼865), intermediate-(n¼232) and high-(n¼75) cardiovascular-risk-groups. KaplanMeier 25-year survival analysis was carried out examining each risk class. The log-rank statistic was used to estimate the survival of subjects with/ without elevated serum Lp(a) levels compared to the population’s median (18 mg/dl). Survival functions were age-adjusted considering the subjects’ starting age (if higher/lower than the study-population's mean, which was 56). Finally, we constructed a ROC curve in order to evaluate whether serum Lp(a) concentration was an independent long-term mortality prognosticator. Results: In the low-cardiovascular-risk-group, no differences were observed in the 25-year survival regarding increased Lp(a) levels. According to the Mantel-Cox test, subjects at intermediate-cardiovascularrisk, aged 56-69 and with elevated Lp(a) levels, showed a significantly higher survival-time-estimate rather than subjects with the same age but lower Lp(a) levels (15,1±0,8vs12,8±1 years, P¼0,01). However, first group’s mortality-rate (60,2%) was higher compared to the second one (39,8%). In the high-cardiovascular-risk-group, having only older subjects than the population's mean prevented us from any statement. Furthermore, in this group, dosing serum Lp(a) appeared a mildly accurate, though predictive, test of long-term mortality (AUC¼0,63,CI[0,50-0,76],P¼0,05, with 17,5mg/ dl best cut-off-value), losing any predictive power in subjects at low-/intermediate-cardiovascular-risk. Conclusions: Tightly controlling modifiable cardiovascular-risk factors is advisable in subjects with high serum Lp(a) levels.
EAS16-0359, LIPOPROTEINS AND LIPID METABOLISM: LP(A). A SYSTEMATIC REVIEW AND META-ANALYSIS COMPARING THE EFFECTS OF STATINS AND FIBRATES ON PLASMA LIPOPROTEIN(A) LEVELS A. Sahebkar 1, L.E. Simental-Mendía 2, M. Banach 3, M.C. Serban 4, G.F. Watts 5. 1 Mashhad University of Medical Sciences, Biotechnology Research Center, Mashhad, Iran; 2 Mexican Social Security Institute, Biomedical Research Unit-, Durango, Mexico; 3 Medical University of Lodz, Department of Hypertension, Lodz, Poland; 4 “Victor Babes” University of Medicine and Pharmacy, Department of Functional Sciences, Timisoara, Romania; 5 Lipid Disorders Clinic- Royal Perth Hospital- School of Medicine and Pharmacology- University of Western Australia, Cardiovascular Medicine, Perth, Australia Objectives: Elevated plasma lipoprotein(a) [Lp(a)] concentration has been suggested as a causal risk factor for coronary heart disease (CHD). Modest reductions in plasma Lp(a) levels have been reported with statins and fibrates but their comparative efficacy is unknown. This study aimed to compare the Lp(a)-lowering activity of statins and fibrates through a meta-analysis of randomized head-to-head trials. Methods: A systematic literature search of was conducted to find randomized head-to-head trials comparing the efficacy of fibrates versus statins in reducing plasma Lp(a) levels. A random-effects model Metaanalysis with inverse variance weighting was applied for the meta-analysis. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were used as summary statistics. Results: Sixteen trials met the inclusion criteria and were included. Metaanalysis revealed a significantly greater effect of fibrates versus statins in lowering plasma Lp(a) concentrations (WMD: -2.70 mg/dL, 95% CI: -4.56, -0.84, p ¼ 0.004). Combination therapy with fibrates and statins had a significantly greater effect compared with statin monotherapy (WMD: -1.60 mg/dL, 95% CI: -2.93, -0.26, p ¼ 0.019) but not fibrate monotehrapy (WMD: -1.76 mg/dL, 95% CI: -5.44, +1.92, p ¼ 0.349) in lowering plasma Lp(a) concentrations.
Conclusions: Fibrates have a higher efficacy in lowering plasma Lp(a) concentrations compared with statins, both in the monotherapy and combination therapy.
EAS16-0389, LIPOPROTEINS AND LIPID METABOLISM: LP(A). DEFINING THE MECHANISM OF LIPOPROTEIN(A) [LP(A)] LOWERING BY ALIROCUMAB IN TRANSGENIC MOUSE MODELS C. Yeang 1, P. Miu 1, S. Green 1, X. Yang 1, M.Y. Hung 2, J.L. Witztum 1, S. Tsimikas 1. 1 University of California - San Diego, Medicine, San Diego, USA; 2 Taipei Medical University, Medicine, Taipei, Taiwan Objectives: Lp(a) consists of apo(a) covalently bound to apoB of LDL. PCSK9 monoclonal antibodies, such as alirocumab, lower Lp(a) in humans by 9-38%, but the mechanisms are not well defined. We utilized transgenic apo(a)/Lp(a) mice to assess how alirocumab lowers Lp(a) in-vivo. Methods: C57BL/6 transgenic mice expressing apo(a) only (under control of an apoE promoter) and double transgenic Lp(a) (expressing both apo(a) and human apoB-100 [hApoB]) were treated with alirocumab or vehicle. Plasma levels of Lp(a), total apo(a) [free and true Lp(a)], and hApoB were quantified by ELISA. Hepatic mRNA levels of apo(a), hApoB, and mApoB were measured in both groups. Finally, plasma clearance of human 125Iapo(a) was determined following intravenous injection to WT mice treated with alirocumab or vehicle. Results: Alirocumab lowered total cholesterol and mApoB 29-62% (p<0.05 for all). hApoB levels were unaffected, possibly due to the low affinity of hApoB for the mouse LDLR. In alirocumab treated apo(a) and Lp(a) mice, total apo(a) levels declined by up to 42% and 41% (p<0.05 for all), respectively. In alirocumab treated Lp(a) mice, Lp(a) levels were unaffected, which we speculate is due to the excess of apo(a) [unassociated with hApoB] in plasma of these mice. Hepatic mRNA levels of apo(a), hApoB and mApoB were not affected by alirocumab. Plasma clearance of intravenously injected 125I-apo(a) was accelerated by 25% in alirocumab treated WT mice vs. vehicle. Conclusions: Alirocumab mediated lowering of plasma apo(a) is due to enhanced clearance. Work is ongoing to identify the receptors and/or pathways involved.
EAS16-0390, LIPOPROTEINS AND LIPID METABOLISM: LP(A). LIPOPROTEIN(A)-CHOLESTEROL (LP(A)-C) LEVELS DETERMINED BY VERTICAL AUTO PROFILE (VAP) CORRELATES WEAKLY WITH LP(A) MASS BUT MODESTLY WITH HDL-C: IMPLICATIONS FOR APPROPRIATE INTERPRETATION OF CLINICAL DATA C. Yeang, S. Tsimikas. University of California - San Diego, Medicine, San Diego, USA Objectives: Lp(a) predicts CVD events and faster progression of aortic stenosis and is a therapeutic target. Lp(a) is generally measured as mass (mg/dL) of the entire particle, of which 30-45% is Lp(a)-C, or as apo(a) particle number (nmol/L). VAP is widely used to estimate Lp(a)-C in patients, but reports suggest that it does not predict CVD. Appropriate Lp(a) measurements are needed for population cutoffs and in ongoing clinical trials of Lp(a) lowering. Methods: Plasma Lp(a) mass, measured by an isoform-independent ELISA, OxPL-apoB, which primarily reflects OxPL on Lp(a), and Lp(a)-C estimated by VAP, were measured in 591 patients at baseline and 24 weeks post therapy with ezetimibe/simvastatin (E/S) (10/20mg) + Niacin (N) (to 2g), E/ S, or N monotherapy in a randomized, double-blind trial of hypercholesterolemic patients. Results: In the entire cohort, Lp(a) mass correlated strongly with OxPLapoB at baseline (r¼0.90, p<0.001) and 24 weeks (r¼0.83, p<0.001); in contrast VAP Lp(a)-C correlated weakly with Lp(a) mass at baseline (r¼0.39, p<0.001) and 24 weeks (r¼0.46, p<0.001),(Figure). Instead, Lp(a)C correlated modestly with HDL-C at baseline (r¼0.55, p<0.001) and 24 weeks (r¼0.58, p<0.01), explaining ~30% of the relationship.
Conclusions: LA can be used safely for pediatric patients with CTE due to elevated Lp(a).
EAS16-0311, LIPOPROTEINS AND LIPID METABOLISM: LP(A). RATIONALE AND DESIGN OF A CLINICAL TRIAL TO ASSESS LP(A) LOWERING WITH IONIS-APO(A)-LRX IN PATIENTS UNDERGOING APHERESIS FOR ELEVATED LP(A) AND RECURRENT CARDIOVASCULAR EVENTS P.M. Moriarty 1, E.S. Thiessen 2, J.L. Witztum 3, N.J. Viney 4, S. Tsimikas 5. 1 University of Kansas Medical Center, Clinical Pharmacology, Kansas City, USA; 2 Charite-Universitaetsm edizin, LIpid Ambulatory Clinic, Berlin, Germany; 3 UCSD, Endocrinology, La Jolla, USA; 4 Ionis Pharmaceuticals, Pharmaceuticals, Carlsbad, USA; 5 USA Objectives: Patients with recurrent major adverse cardiovascular events (MACE), controlled LDL-C but Lp(a) >60 mg/dL are treated with Lipoprotein-Apheresis (LA) in Germany and ad hoc elsewhere. LA results in 60-80% MACE reduction and in 60-80% acute reduction of Lp(a). However, due to rapid liver production the time-averaged Lp(a) reduction is only 30-35%. More potent Lp(a)-lowering agents are needed to prevent MACE in highrisk patients. Methods: IONIS-APO(a)-LRx, an optimized second generation antisense oligonucleotide (ASO) that also contains an N-acetylgalactosamine moiety targeted to the hepatocyte asialoglycoprotein receptor, has a ~32X higher potency compared to the unconjugated ASO. In prior studies, volunteers with Lp(a) >30mg/dL treated with single doses of 10, 20, 40 and 80mg subcutaneously had -26%, -33%, -44% and -79% mean percentage reductions in Lp(a), respectively, and with multiple doses (6 doses over 22 days) of 10, 20 and 40mg had -66%, -82% and -92% reductions, respectively (p0.001 for all). Results: Patients on weekly or bi-weekly LA will be assessed for timeaveraged percent reductions in Lp(a) over a 1-month period. LA will then be replaced by weekly dosing of 30mg IONIS-APO(a)-LRx for 13 weeks and followed for another 16 weeks. The primary endpoint will be the difference in the mean time-averaged reduction in Lp(a) on LA vs. IONIS-APO(a)-LRx. Other endpoints include reduction in oxidized phospholipids on apoB at 13 weeks and time to reinstitution of LA in the follow-up period. Conclusions: IONIS-APO(a)-LRx has the potential to produce greater reductions in Lp(a) and enhance quality of life compared to Lipid Apheresis.
EAS16-0314, LIPOPROTEINS AND LIPID METABOLISM: LP(A). PREVALENCE OF LPA SINGLE NUCLEOTIDE POLYMORPHISMS AND ISOFORMS IN PATIENTS ENROLLED IN A PHASE 2 IONIS-APO(A)RX CLINICAL TRIAL E.S. Stroes 1, F.M. van der Valk 1, D. Gaudet 2, I. Gouni-Berthold 3, N.P. Riksen 4, E. Steinhagen-Thiessen 5, B. Isermann 6, B. Nordestgaard 7, N.J. Viney 8, S. Marcovina 9, S.G. Hughes 8, J. Tami 10, S. Xia 11, J.L. Witztum 12, S. Tsimikas 13. 1 Academic Medical Center- Amsterdam, Medicine, Amsterdam, Netherlands; 2 Universite de Montreal and Ecogene21 Clinical Reserach centre, Medicine, Chicoutimi, Canada; 3 University of Cologne, Medicine, Cologne, Germany; 4 Rabdoud University Medical Centre, Medicine, Nijmegen, Netherlands; 5 Lipid Ambulatory ClinicCharite-Universitaetsm edizin, Medicine, Berlin, Germany; 6 6Institut für klinische chemie und Biochemie- Lipidambulanz- Germany, Medicine, Magdeburg, Germany; 7 Herlev Hospital- Copenhagen University HospitalUniversity of Copenhagen- Denmark, Medicine, Copenhagen, Denmark; 8 Ionis Pharmaceuticals- Carlsbad- CA, Pharmaceuticals, Carlsbad, USA; 9 University of Washington- Seattle- WA, Medicine, Seattle, USA; 10 Ionis Pharmaceuticals, Pharmaceuticals, Carlesbad, USA; 11 Ionis Pharmaceuticals, Pharmaceuticals, Carlsbad, USA; 12 UCSD, Medicine/endocrinology, La Jolla, USA; 13 USA Objectives: Elevated Lp(a) is an independent predictor of CVD and aortic stenosis. Lp(a) levels are genetically determined by apo(a) isoforms, and by single nucleotide polymorphisms (snps) rs10455872 and rs3798220 in European communities (prevalence ~7-15% and ~3%, respectively). The
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distribution in patients eligible for clinical trials of Lp(a) lowering is unknown Methods: A phase 2 study (n¼64) randomizing patients with Lp(a) 125438 nmol/L (~50-175 mg/dL) or 438 nmol/L (~175 mg/dL), representing the 80th and >99th percentile of Lp(a), was conducted with IONISAPO(a)Rx [previously called ISIS-APO(a)Rx], an antisense oligonucleotide to apo(a). The size of the major apo(a) isoform was available in 63 patients and rs3798220 and rs10455872 in 60 patients Results: Patients were recruited from high-risk lipid clinics in Canada and Europe. Average age was 55, 48.4% female, 96.9% white, and 36.9% had history of CVD. Mean (range) LDL-C was 122 (49-238) mg/dL, median (range) Lp(a) was 276 (140-803) nmol/L and mean size (range) of apo(a) isoforms was 16.7 (12-20) KIV repeats. 46/60 (76.7%) of patients had risk alleles of rs3798220 and/or rs10455872: 20 (33.3%) rs3798220 and 18 (30.0%) s10455872 heterozygotes, 4 (6.7%) compound heterozygotes, and 1 (1.7%) s3798220 and 3 (5.0%) rs10455872 homozygotes, respectively. 10/11 (90.9%) patients with Lp(a) 438 nmol/L had snps rs3798220 and/or rs10455872. The highest Lp(a) levels were present in homozygotes/compound heterozygotes or 12-16 KIV repeats Conclusions: Patients with elevated Lp(a) (125 nmol/L or ~50 mg/dL) generally had 20 KIV repeats and were more likely to be carriers of rs10455872 and rs3798220 relative to historical community controls
EAS16-0315, LIPOPROTEINS AND LIPID METABOLISM: LP(A). NATURAL TEMPORAL VARIABILITY IN LP(A) LEVELS IN PATIENTS ENROLLED IN THE PLACEBO ARMS OF IONIS-APO(A)RX ANTISENSE OLIGONUCLEOTIDE CLINICAL TRIALS N.J. Viney 1, S. Marcovina 2, J. Tami 3, S. Xia 3, J.L. Witztum 4, S. Tsimikas 5. 1 Ionis Pharmaceuticals, Pharmaceuticals, Carlsbad, USA; 2 University of Washington- Seattle- WA, Medicine, Seattle, USA; 3 Ionis Pharmaceuticals, Pharmaceutical, Carlsbad, USA; 4 UCSD, Medicine/ endocrinology, La Jolla, USA; 5 USA Objectives: Lp(a) levels are thought to fluctuate minimally, but this is not well studied Methods: The temporal variability in Lp(a) levels was evaluated in placebo groups of IONIS-APO(a)Rx, a generation 2+ ASO : Study 1- in normal volunteers [n¼4 for single ascending dose (SAD) and n¼6 for multiple (MAD) cohorts] with Lp(a) ~25 nmol/L(~10 mg/dL); and Study 2- patients (n¼29) with Lp(a) 125 nmol/L(~50 mg/dL). Serial blood samples (range 7-12) were obtained over 30-190 days. Lp(a) was measured at the Northwest Lipid Metabolism and Diabetes Research Laboratories Results: The median(IQR) baseline Lp(a) was 18 (11, 50) nmol/L for SAD, 166 (101, 205) nmol/L for MAD in Study 1, and 223 (188, 360) nmol/L in Study 2. The greatest variability at any timepoint was -18 to +19 nmol/L for SAD, -93 to +22 nmol/L for MAD in Study 1 and -125 to +101 nmol/L in Study 2, respectively. Evaluated as %D from baseline, variability was -65 to +100% for SAD, -36 to +62% for MAD in Study 1 and -37 to +54 % in Study 2. In study 1, the mean % of timepoints that vary <¼20% were 60% for SAD, 82% for MAD, and in Study 2 89%. There were 3(75%) outliers (defined as >20% difference from baseline at any timepoint) for SAD and 3(50%) for MAD in Study 1, and 14(48%) in Study 2 Conclusions: The natural variability of Lp(a) is more apparent in subjects with low vs. high levels, consistent with a strong genetic influence in plasma levels
EAS16-0330, LIPOPROTEINS AND LIPID METABOLISM: LP(A). PROGNOSTIC VALUE OF SERUM LIPOPROTEIN(A) LEVELS ON LONGTERM MORTALITY IN A LARGE SAMPLE OF SUBJECTS IN PRIMARY CARDIOVASCULAR PREVENTION: DATA FROM THE BRISIGHELLA HEART STUDY F. Fogacci, S. D'Addato, A.F.G. Cicero, E. Bertagnin, S. Palmisano, L. D'Agostini, E. Grandi, M. Giovannini, C. Borghi. Alma Mater Studiorum University of Bologna, Department of Medical and Surgical Sciences, Bologna, Italy
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Abstracts / Atherosclerosis 252 (2016) e1ee196
Objectives: To assess whether serum Lp(a) levels can significantly influence long-term survival in subjects with an equal general cardiovascularrisk-profile. Methods: This study involved a Brisighella Heart Study cohort sample of 1172 adult subjects (M:573;F:599; aged 40-69) with no cardiovasculardiseases at enrollment. According to the CUORE project risk-charts (Italianspecific risk-charts), individuals were stratified into low-(n¼865), intermediate-(n¼232) and high-(n¼75) cardiovascular-risk-groups. KaplanMeier 25-year survival analysis was carried out examining each risk class. The log-rank statistic was used to estimate the survival of subjects with/ without elevated serum Lp(a) levels compared to the population’s median (18 mg/dl). Survival functions were age-adjusted considering the subjects’ starting age (if higher/lower than the study-population's mean, which was 56). Finally, we constructed a ROC curve in order to evaluate whether serum Lp(a) concentration was an independent long-term mortality prognosticator. Results: In the low-cardiovascular-risk-group, no differences were observed in the 25-year survival regarding increased Lp(a) levels. According to the Mantel-Cox test, subjects at intermediate-cardiovascularrisk, aged 56-69 and with elevated Lp(a) levels, showed a significantly higher survival-time-estimate rather than subjects with the same age but lower Lp(a) levels (15,1±0,8vs12,8±1 years, P¼0,01). However, first group’s mortality-rate (60,2%) was higher compared to the second one (39,8%). In the high-cardiovascular-risk-group, having only older subjects than the population's mean prevented us from any statement. Furthermore, in this group, dosing serum Lp(a) appeared a mildly accurate, though predictive, test of long-term mortality (AUC¼0,63,CI[0,50-0,76],P¼0,05, with 17,5mg/ dl best cut-off-value), losing any predictive power in subjects at low-/intermediate-cardiovascular-risk. Conclusions: Tightly controlling modifiable cardiovascular-risk factors is advisable in subjects with high serum Lp(a) levels.
EAS16-0359, LIPOPROTEINS AND LIPID METABOLISM: LP(A). A SYSTEMATIC REVIEW AND META-ANALYSIS COMPARING THE EFFECTS OF STATINS AND FIBRATES ON PLASMA LIPOPROTEIN(A) LEVELS A. Sahebkar 1, L.E. Simental-Mendía 2, M. Banach 3, M.C. Serban 4, G.F. Watts 5. 1 Mashhad University of Medical Sciences, Biotechnology Research Center, Mashhad, Iran; 2 Mexican Social Security Institute, Biomedical Research Unit-, Durango, Mexico; 3 Medical University of Lodz, Department of Hypertension, Lodz, Poland; 4 “Victor Babes” University of Medicine and Pharmacy, Department of Functional Sciences, Timisoara, Romania; 5 Lipid Disorders Clinic- Royal Perth Hospital- School of Medicine and Pharmacology- University of Western Australia, Cardiovascular Medicine, Perth, Australia Objectives: Elevated plasma lipoprotein(a) [Lp(a)] concentration has been suggested as a causal risk factor for coronary heart disease (CHD). Modest reductions in plasma Lp(a) levels have been reported with statins and fibrates but their comparative efficacy is unknown. This study aimed to compare the Lp(a)-lowering activity of statins and fibrates through a meta-analysis of randomized head-to-head trials. Methods: A systematic literature search of was conducted to find randomized head-to-head trials comparing the efficacy of fibrates versus statins in reducing plasma Lp(a) levels. A random-effects model Metaanalysis with inverse variance weighting was applied for the meta-analysis. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were used as summary statistics. Results: Sixteen trials met the inclusion criteria and were included. Metaanalysis revealed a significantly greater effect of fibrates versus statins in lowering plasma Lp(a) concentrations (WMD: -2.70 mg/dL, 95% CI: -4.56, -0.84, p ¼ 0.004). Combination therapy with fibrates and statins had a significantly greater effect compared with statin monotherapy (WMD: -1.60 mg/dL, 95% CI: -2.93, -0.26, p ¼ 0.019) but not fibrate monotehrapy (WMD: -1.76 mg/dL, 95% CI: -5.44, +1.92, p ¼ 0.349) in lowering plasma Lp(a) concentrations.
Conclusions: Fibrates have a higher efficacy in lowering plasma Lp(a) concentrations compared with statins, both in the monotherapy and combination therapy.
EAS16-0389, LIPOPROTEINS AND LIPID METABOLISM: LP(A). DEFINING THE MECHANISM OF LIPOPROTEIN(A) [LP(A)] LOWERING BY ALIROCUMAB IN TRANSGENIC MOUSE MODELS C. Yeang 1, P. Miu 1, S. Green 1, X. Yang 1, M.Y. Hung 2, J.L. Witztum 1, S. Tsimikas 1. 1 University of California - San Diego, Medicine, San Diego, USA; 2 Taipei Medical University, Medicine, Taipei, Taiwan Objectives: Lp(a) consists of apo(a) covalently bound to apoB of LDL. PCSK9 monoclonal antibodies, such as alirocumab, lower Lp(a) in humans by 9-38%, but the mechanisms are not well defined. We utilized transgenic apo(a)/Lp(a) mice to assess how alirocumab lowers Lp(a) in-vivo. Methods: C57BL/6 transgenic mice expressing apo(a) only (under control of an apoE promoter) and double transgenic Lp(a) (expressing both apo(a) and human apoB-100 [hApoB]) were treated with alirocumab or vehicle. Plasma levels of Lp(a), total apo(a) [free and true Lp(a)], and hApoB were quantified by ELISA. Hepatic mRNA levels of apo(a), hApoB, and mApoB were measured in both groups. Finally, plasma clearance of human 125Iapo(a) was determined following intravenous injection to WT mice treated with alirocumab or vehicle. Results: Alirocumab lowered total cholesterol and mApoB 29-62% (p<0.05 for all). hApoB levels were unaffected, possibly due to the low affinity of hApoB for the mouse LDLR. In alirocumab treated apo(a) and Lp(a) mice, total apo(a) levels declined by up to 42% and 41% (p<0.05 for all), respectively. In alirocumab treated Lp(a) mice, Lp(a) levels were unaffected, which we speculate is due to the excess of apo(a) [unassociated with hApoB] in plasma of these mice. Hepatic mRNA levels of apo(a), hApoB and mApoB were not affected by alirocumab. Plasma clearance of intravenously injected 125I-apo(a) was accelerated by 25% in alirocumab treated WT mice vs. vehicle. Conclusions: Alirocumab mediated lowering of plasma apo(a) is due to enhanced clearance. Work is ongoing to identify the receptors and/or pathways involved.
EAS16-0390, LIPOPROTEINS AND LIPID METABOLISM: LP(A). LIPOPROTEIN(A)-CHOLESTEROL (LP(A)-C) LEVELS DETERMINED BY VERTICAL AUTO PROFILE (VAP) CORRELATES WEAKLY WITH LP(A) MASS BUT MODESTLY WITH HDL-C: IMPLICATIONS FOR APPROPRIATE INTERPRETATION OF CLINICAL DATA C. Yeang, S. Tsimikas. University of California - San Diego, Medicine, San Diego, USA Objectives: Lp(a) predicts CVD events and faster progression of aortic stenosis and is a therapeutic target. Lp(a) is generally measured as mass (mg/dL) of the entire particle, of which 30-45% is Lp(a)-C, or as apo(a) particle number (nmol/L). VAP is widely used to estimate Lp(a)-C in patients, but reports suggest that it does not predict CVD. Appropriate Lp(a) measurements are needed for population cutoffs and in ongoing clinical trials of Lp(a) lowering. Methods: Plasma Lp(a) mass, measured by an isoform-independent ELISA, OxPL-apoB, which primarily reflects OxPL on Lp(a), and Lp(a)-C estimated by VAP, were measured in 591 patients at baseline and 24 weeks post therapy with ezetimibe/simvastatin (E/S) (10/20mg) + Niacin (N) (to 2g), E/ S, or N monotherapy in a randomized, double-blind trial of hypercholesterolemic patients. Results: In the entire cohort, Lp(a) mass correlated strongly with OxPLapoB at baseline (r¼0.90, p<0.001) and 24 weeks (r¼0.83, p<0.001); in contrast VAP Lp(a)-C correlated weakly with Lp(a) mass at baseline (r¼0.39, p<0.001) and 24 weeks (r¼0.46, p<0.001),(Figure). Instead, Lp(a)C correlated modestly with HDL-C at baseline (r¼0.55, p<0.001) and 24 weeks (r¼0.58, p<0.01), explaining ~30% of the relationship.