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Lp(a) (Lipoprotein(a)) Levels Predict Progression of Carotid Atherosclerosis in Subjects With Atherosclerotic Cardiovascular Disease on Intensive Lipid Therapy: An Analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) Carotid Magnetic Resonance Imaging Substudy-Brief Report.
Hippe, DS, Phan, BAP, Sun, J, Isquith, DA, O'Brien, KD, Crouse, JR, Anderson, T, Huston, J, Marcovina, SM, Hatsukami, TS, et al
Arteriosclerosis, thrombosis, and vascular biology. 2018;(3):673-678
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Abstract
OBJECTIVE To assess whether Lp(a) (lipoprotein(a)) levels and other lipid levels were predictive of progression of atherosclerosis burden as assessed by carotid magnetic resonance imaging in subjects who have been treated with LDL-C (low-density lipoprotein cholesterol)-lowering therapy and participated in the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes). APPROACH AND RESULTS AIM-HIGH was a randomized, double-blind study of subjects with established vascular disease, elevated triglycerides, and low HDL-C (high-density lipoprotein cholesterol). One hundred fifty-two AIM-HIGH subjects underwent both baseline and 2-year follow-up carotid artery magnetic resonance imaging. Plaque burden was measured by the percent wall volume (%WV) of the carotid artery. Associations between annualized change in %WV with baseline and on-study (1 year) lipid variables were evaluated using multivariate linear regression and the Bonferroni correction to account for multiple comparisons. Average %WV at baseline was 41.6±6.8% and annualized change in %WV over 2 years ranged from -3.2% to 3.7% per year (mean: 0.2±1.1% per year; P=0.032). Increases in %WV were significantly associated with higher baseline Lp(a) (β=0.34 per 1-SD increase of Lp(a); 95% confidence interval, 0.15-0.52; P<0.001) after adjusting for clinical risk factors and other lipid levels. On-study Lp(a) had a similar positive association with %WV progression (β=0.33; 95% confidence interval, 0.15-0.52; P<0.001). CONCLUSIONS Despite intensive lipid therapy, aimed at aggressively lowering LDL-C to <70 mg/dL, carotid atherosclerosis continued to progress as assessed by carotid magnetic resonance imaging and that elevated Lp(a) levels were independent predictors of increases in atherosclerosis burden.
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Effect of alirocumab on lipids and lipoproteins in individuals with metabolic syndrome without diabetes: Pooled data from 10 phase 3 trials.
Henry, RR, Müller-Wieland, D, Taub, PR, Bujas-Bobanovic, M, Louie, MJ, Letierce, A, Ginsberg, HN
Diabetes, obesity & metabolism. 2018;(7):1632-1641
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Abstract
AIMS: This analysis assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in patients with or without metabolic syndrome (MetS) using pooled data from 10 phase 3 ODYSSEY trials. MATERIALS AND METHODS Data from 4983 randomized patients (1940 with MetS; 1642 with diabetes excluded) were assessed in subgroups by MetS status. Efficacy data were analysed in 4 pools per study design: 2 placebo-controlled pools (1 using alirocumab 150 mg every 2 weeks [Q2W], 1 using 75/150 mg Q2W) with background statin, and 2 ezetimibe-controlled pools (both alirocumab 75/150 mg Q2W), 1 with and 1 without background statin. Alirocumab 75/150 mg indicates possible dose increase from 75 to 150 mg at Week 12 based on Week 8 LDL-C. RESULTS LDL-C percentage reduction from baseline at Week 24 with alirocumab was 63.9% (MetS) and 56.8% (non-MetS) in the pool of alirocumab 150 mg Q2W, and 42.2% to 52.2% (MetS) and 45.0% to 52.6% (non-MetS) in 3 pools using 75/150 mg Q2W. Levels of other lipid and lipoprotein parameters were also improved with alirocumab treatment, including apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein(a) and HDL-C. Overall, the percentage change at Week 24 in LDL-C and other lipids and lipoproteins did not vary by MetS status. Adverse event rates were generally similar between treatment groups, regardless of MetS status; injection-site reactions occurred more frequently in alirocumab vs control groups. CONCLUSIONS Across study pools, alirocumab-associated reductions in LDL-C, apolipoprotein B, and non-HDL-C were significant vs control, and did not vary by MetS status.
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Lipoprotein(a) level and MIF gene variant predict incident metabolic syndrome and mortality.
Onat, A, Can, G, Çoban, N, Dönmez, İ, Çakır, H, Ademoğlu, E, Erginel-Ünaltuna, N, Yüksel, H
Journal of investigative medicine : the official publication of the American Federation for Clinical Research. 2016;(2):392-9
Abstract
Owing to the scarcity of available information, we aimed to assess the association of migration inhibitory factor (MIF)-173 G/C genotypes and serum lipoprotein(Lp)(a) with incident metabolic syndrome (MetS) and all-cause mortality, respectively. In population based, middle-aged adults (n=1297), stratified by gender and presence of MetS, we used Lp(a) quintiles to identify non-linear associations with outcomes using Cox regression models, adjusted for MIF genotype, age, smoking status, high density lipoprotein cholesterol, and systolic blood pressure. After 5.2 years of follow-up, 151 cases of incident MetS and 123 deaths were recorded. For incident MetS, adjusted HRs increased in each gender across four declining quintiles, starting from the highest quintile in men and from quintile 4 in women. The MIF CC-GC genotype appeared to contribute to the risk estimates in men. Similarly adjusted models in the whole sample disclosed that all-cause mortality tended to be inversely associated with Lp(a) quintiles and yielded an HR (2.42 (95% CI 1.03 to 5.81)) in men in quintile 2, whereas the MIF genotype additively predicted mortality (HR 1.79 (95% CI 1.01 to 3.18)) only in men. Excess risk of death was additively conferred on Turkish men by the MIF CC-GC genotype and by apparently reduced circulating Lp(a) assays, supporting the notion that 'low' serum Lp(a), mediating autoimmune activation, is a major determinant of metabolic disease risk and death. Damaged MIF protein and more complex autoimmune activation in women may be responsible from lack of relationship to MetS/mortality.
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Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes).
Albers, JJ, Slee, A, O'Brien, KD, Robinson, JG, Kashyap, ML, Kwiterovich, PO, Xu, P, Marcovina, SM
Journal of the American College of Cardiology. 2013;(17):1575-9
Abstract
OBJECTIVES This study sought to examine the relationship between baseline and on-study apolipoproteins (apo) A-1 and B and lipoprotein(a) [Lp(a)] levels and the development of subsequent cardiovascular (CV) events in the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes) trial. BACKGROUND Niacin has been reported to lower apoB and Lp(a) and to raise apoA-1. METHODS Individuals with CV disease and low baseline levels of high-density lipoprotein cholesterol were randomized to simvastatin plus placebo or simvastatin, plus extended-release niacin ([ERN], 1,500 to 2,000 mg/day), with ezetimibe added as needed, in both groups, to maintain an on-treatment low-density lipoprotein cholesterol in the range of 40 to 80 mg/dl. Hazard ratios (HRs) were used to evaluate the relationship between levels of apoA-1, apoB, and Lp(a), and CV events in each treatment group. RESULTS Baseline apoB and the apoB/apoA-I ratio were significantly predictive of CV events only for the placebo group (HR: 1.17 [p = 0.018] and HR: 1.19 [p = 0.016]). Baseline and on-study Lp(a) were predictive of CV events in both simvastatin plus placebo (baseline HR: 1.24 [p = 0.002] and on-study HR: 1.21 [p = 0.017]) and the simvastatin plus ERN group (baseline HR: 1.25 [p = 0.001] and on-study HR: 1.18 [p = 0.028]). The ERN modestly increased 1-year apoA-1 (7%), decreased apoB (13%), decreased the ApoB/ApoA-1 ratio (19%), and decreased Lp(a) 21%, but did not reduce CV events. CONCLUSIONS Lp(a) was associated with increased CV risk in both treatment groups indicating that it contributes to residual CV risk. However, there was no evidence that ERN reduced CV risk, despite favorable lipoprotein changes.
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Lp(a) and lipids in adult Turner's syndrome: impact of treatment with 17beta-estradiol and norethisterone.
Gravholt, CH, Christian Klausen, I, Weeke, J, Sandahl Christiansen, J
Atherosclerosis. 2000;(1):201-8
Abstract
Turner's syndrome is associated with a high incidence of cardiovascular disease and hypothyreosis; conditions which are associated with abnormal lipid metabolism. To test whether alterations of lipid metabolism is present in healthy Turner's women, we compared lipids in a group of adult women with Turner's syndrome with an age matched group of healthy women. In addition the impact of sex steroid replacement therapy was studied in the women with Turner's syndrome. Patients were studied before and during treatment with hormonal replacement therapy, consisting of either oral 17beta-estradiol or transdermal 17beta-estradiol, and oral norethisterone. Control subjects were studied once in the early follicular stage of the menstrual cycle. The study group consisted of 26 (33.2+/-7.9 years) patients with Turner's syndrome and an age matched control group of 24 (32.7+/-7.6 years) normal women. Body composition measures, apolipoprotein (apo) B and apo A-I, Lp(a), cholesterol, HDL, LDL, triglycerides, thyroxine (TT4), free thyroxine (FT4), triiodothyronine (TT3), free triiodothyronine (FT3), TSH, and leptin were determined. Apo A-I levels were higher in Turner's patients (P45 g/l) Lp(a), more women with Turner's syndrome had high levels of Lp(a) than controls (P=0.024), while all other measures of lipid metabolism were comparable to controls. The level of TSH, FT3, and FT4 were significantly higher in Turner's patients, while TT4, TT3 and adjusted 24h energy expenditure were comparable to controls. Lp(a) (P=0.005), HDL (P=0.045) and apo A-I (P=0.039) decreased significantly, while there was a tendency towards a decrease in apo B (P=0.063) during treatment with sex hormones. In conclusion more women with Turner's syndrome than controls have high levels of apolipoprotein A-I and Lp(a), but only after dichomitization, while other markers of lipid metabolism are normal. Replacement therapy with female sex hormones lowered Lp(a), HDL cholesterol and apolipoprotein A-I.