| 1. |
- Locke, Adam E, et al.
(författare)
-
Genetic studies of body mass index yield new insights for obesity biology.
- 2015
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
-
Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
|
|
| 2. |
- Asselbergs, Folkert W., et al.
(författare)
-
Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci
- 2012
-
Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 91:5, s. 823-838
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering similar to 2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
|
|
| 3. |
- Teslovich, Tanya M., et al.
(författare)
-
Biological, clinical and population relevance of 95 loci for blood lipids
- 2010
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7307, s. 707-713
-
Tidskriftsartikel (refereegranskat)abstract
- Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
|
|
| 4. |
- Tragante, Vinicius, et al.
(författare)
-
Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci.
- 2014
-
Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:3, s. 349-360
-
Tidskriftsartikel (refereegranskat)abstract
- Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.
|
|
| 5. |
- Ganesh, Santhi K., et al.
(författare)
-
Loci influencing blood pressure identified using a cardiovascular gene-centric array
- 2013
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:8, s. 1663-1678
-
Tidskriftsartikel (refereegranskat)abstract
- Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped 50 000 single-nucleotide polymorphisms (SNPs) that capture variation in 2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P 2.4 10(6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
|
|
| 6. |
- Do, Ron, et al.
(författare)
-
Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
-
Tidskriftsartikel (refereegranskat)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
|
|
| 7. |
- Schunkert, Heribert, et al.
(författare)
-
Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
- 2011
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:4, s. 153-333
-
Tidskriftsartikel (refereegranskat)abstract
- We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 x 10(-8) and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
|
|
| 8. |
- Willer, Cristen J., et al.
(författare)
-
Discovery and refinement of loci associated with lipid levels
- 2013
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1274-1283
-
Tidskriftsartikel (refereegranskat)abstract
- Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 x 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
|
|
| 9. |
- Sarwar, Nadeem, et al.
(författare)
-
Interleukin-6 receptor pathways in coronary heart disease : a collaborative meta-analysis of 82 studies
- 2012
-
Ingår i: The Lancet. - New York, NY, USA : Elsevier. - 0140-6736 .- 1474-547X. ; 379:9822, s. 1205-1213
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings: The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele >= 0.04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34.3% (95% CI 30.4-38.2) and of interleukin 6 by 14.6% (10.7-18.4), and mean concentration of C-reactive protein was reduced by 7.5% (5.9-9.1) and of fibrinogen by 1.0% (0.7-1.3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3.4% (1.8-5.0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.
|
|
| 10. |
- Postmus, Iris, et al.
(författare)
-
Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.
- 2014
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5
-
Tidskriftsartikel (refereegranskat)abstract
- Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
|
|
| 11. |
- Peden, John F., et al.
(författare)
-
A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease
- 2011
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:4, s. 339-344
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified 11 common variants convincingly associated with coronary artery disease (CAD)(1-7), a modest number considering the apparent heritability of CAD(8). All of these variants have been discovered in European populations. We report a meta-analysis of four large genome-wide association studies of CAD, with similar to 575,000 genotyped SNPs in a discovery dataset comprising 15,420 individuals with CAD (cases) (8,424 Europeans and 6,996 South Asians) and 15,062 controls. There was little evidence for ancestry-specific associations, supporting the use of combined analyses. Replication in an independent sample of 21,408 cases and 19,185 controls identified five loci newly associated with CAD (P < 5 x 10(-8) in the combined discovery and replication analysis): LIPA on 10q23, PDGFD on 11q22, ADAMTS7-MORF4L1 on 15q25, a gene rich locus on 7q22 and KIAA1462 on 10p11. The CAD-associated SNP in the PDGFD locus showed tissue-specific cis expression quantitative trait locus effects. These findings implicate new pathways for CAD susceptibility.
|
|
| 12. |
|
|
| 13. |
- Vallejo-Vaz, Antonio J., et al.
(författare)
-
Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)
- 2018
-
Ingår i: Atherosclerosis. - : ELSEVIER IRELAND LTD. - 0021-9150 .- 1879-1484. ; 277, s. 234-255
-
Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Management of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries. Methods: Lead Investigators from countries formally involved in the EAS FHSC by mid-May 2018 were invited to provide a brief report on FH status in their countries, including available information, programmes, initiatives, and management. Results: 63 countries provided reports. Data on FH prevalence are lacking in most countries. Where available, data tend to align with recent estimates, suggesting a higher frequency than that traditionally considered. Low rates of FH detection are reported across all regions. National registries and education programmes to improve FH awareness/knowledge are a recognised priority, but funding is often lacking. In most countries, diagnosis primarily relies on the Dutch Lipid Clinics Network criteria. Although available in many countries, genetic testing is not widely implemented (frequent cost issues). There are only a few national official government programmes for FH. Under-treatment is an issue. FH therapy is not universally reimbursed. PCSK9-inhibitors are available in similar to 2/3 countries. Lipoprotein-apheresis is offered in similar to 60% countries, although access is limited. Conclusions: FH is a recognised public health concern. Management varies widely across countries, with overall suboptimal identification and under-treatment. Efforts and initiatives to improve FH knowledge and management are underway, including development of national registries, but support, particularly from health authorities, and better funding are greatly needed.
|
|
| 14. |
- Stitziel, Nathan O, et al.
(författare)
-
Exome Sequencing and Directed Clinical Phenotyping Diagnose Cholesterol Ester Storage Disease Presenting as Autosomal Recessive Hypercholesterolemia.
- 2013
-
Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 33:12, s. 2909-2914
-
Tidskriftsartikel (refereegranskat)abstract
- Autosomal recessive hypercholesterolemia is a rare inherited disorder, characterized by extremely high total and low-density lipoprotein cholesterol levels, that has been previously linked to mutations in LDLRAP1. We identified a family with autosomal recessive hypercholesterolemia not explained by mutations in LDLRAP1 or other genes known to cause monogenic hypercholesterolemia. The aim of this study was to identify the molecular pathogenesis of autosomal recessive hypercholesterolemia in this family.
|
|
| 15. |
- Vallejo-Vaz, Antonio J., et al.
(författare)
-
Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes: Rationale and design of the global EAS Familial Hypercholesterolaemia Studies Collaboration
- 2016
-
Ingår i: Atherosclerosis Supplements. - : ELSEVIER IRELAND LTD. - 1567-5688 .- 1878-5050. ; 22
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The potential for global collaborations to better inform public health policy regarding major non-hypercholesterolaemia (FH), a common genetic disorder associated with premature cardiovascular disease, is yet to be reliably ascertained using similar approaches. The European Atherosclerosis Society FH Studies Collaboration (EAS FHSC) is a new initiative of international stakeholders which will help establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide. Methods: The EAS FHSC will maximise the potential exploitation of currently available and future FH data (retrospective and prospective) by bringing together regional/national/international data sources with access to individuals with a clinical and/or genetic diagnosis of heterozygous or homozygous FH. A novel bespoke electronic platform and FH Data Warehouse will be developed to allow secure data sharing, validation, cleaning, pooling, harmonisation and analysis irrespective of the source or format. Standard statistical procedures will allow us to investigate cross-sectional associations, patterns of real-world practice, trends over time, and analyse risk and outcomes (e.g. cardiovascular outcomes, all-cause death), accounting for potential confounders and subgroup effects. Conclusions: The EAS FHSC represents an excellent opportunity to integrate individual efforts across the world to tackle the global burden of FH. The information garnered from the registry will help reduce gaps in knowledge, inform best practices, assist in clinical trials design, support clinical guidelines and policies development, and ultimately improve the care of FH patients. (C) 2016 Elsevier Ireland Ltd.
|
|
| 16. |
- Faergeman, Ole, et al.
(författare)
-
Plasma Triglycerides and Cardiovascular Events in the Treating to New Targets and Incremental Decrease in End-Points Through Aggressive Lipid Lowering Trials of Statins in Patients With Coronary Artery Disease
- 2009
-
Ingår i: AMERICAN JOURNAL OF CARDIOLOGY. - : Elsevier BV. - 0002-9149. ; 104:4, s. 459-463
-
Tidskriftsartikel (refereegranskat)abstract
- We determined the ability of in-trial measurements of triglycerides (TGs) to predict new cardiovascular events (CVEs) using data from the Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) and Treating to New Targets (TNT) trials. The trials compared atorvastatin 80 mg/day with moderate-dose statin therapy (simvastatin 20 to 40 mg/day in IDEAL and atorvastatin 10 mg/day in TNT) in patients with clinically evident coronary heart disease or a history of myocardial infarction. The outcome measurement in the present research was CVE occurring after the first year of the trial. After adjusting for age, gender, and study, risk of CVEs increased with increasing TGs (p andlt;0.001 for trend across quintiles of TGs). Patients in the highest quintile had a 63% higher rate of CVEs than patients in the lowest quintile (hazard ratio 1.63, 95% confidence interval 1.46 to 1.81) and the relation of TGs to risk was apparent even within the normal range of TGs. The ability of TG measurements to predict risk decreased when high-density lipoprotein cholesterol and apolipoprotein B:apolipoprotein A-I were included in the statistical analysis, and it was abolished with inclusion of further variables (diabetes, body mass index, glucose, hypertension, and smoking; (p = 0.044 and 0.621, respectively, for trend across quintiles of TGs). Similar results were obtained in patients in whom low-density lipoprotein cholesterol had been lowered to guideline-recommended levels. In conclusion, even slightly increased TG levels are associated with higher risk of recurrence of CVEs in statin-treated patients and should be considered a useful marker of risk.
|
|
| 17. |
- Holleboom, Adriaan G, et al.
(författare)
-
Heterozygosity for a Loss-of-Function Mutation in GALNT2 Improves Plasma Triglyceride Clearance in Man
- 2011
-
Ingår i: Cell Metabolism. - : Elsevier. - 1550-4131 .- 1932-7420. ; 14:6, s. 811-8
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified GALNT2 as a candidate gene in lipid metabolism, but it is not known how the encoded enzyme ppGalNAc-T2, which contributes to the initiation of mucin-type O-linked glycosylation, mediates this effect. In two probands with elevated plasma high-density lipoprotein cholesterol and reduced triglycerides, we identified a mutation in GALNT2. It is shown that carriers have improved postprandial triglyceride clearance, which is likely attributable to attenuated glycosylation of apolipoprotein (apo) C-III, as observed in their plasma. This protein inhibits lipoprotein lipase (LPL), which hydrolyses plasma triglycerides. We show that an apoC-III-based peptide is a substrate for ppGalNAc-T2 while its glycosylation by the mutant enzyme is impaired. In addition, neuraminidase treatment of apoC-III which removes the sialic acids from its glycan chain decreases its potential to inhibit LPL. Combined, these data suggest that ppGalNAc-T2 can affect lipid metabolism through apoC-III glycosylation, thereby establishing GALNT2 as a lipid-modifying gene.
|
|
| 18. |
- Holme, Ingar, et al.
(författare)
-
Adherence-adjusted efficacy with intensive versus standard statin therapy in patients with acute myocardial infarction in the IDEAL study
- 2009
-
Ingår i: EUROPEAN JOURNAL OF CARDIOVASCULAR PREVENTION and REHABILITATION. - 1741-8267. ; 16:3, s. 315-320
-
Tidskriftsartikel (refereegranskat)abstract
- Background The Incremental Decrease in End Points through Aggressive Lipid Lowering trial showed that the primary endpoint major coronary event was reduced by 11% (0.78-1.01) using atorvastatin 80 mg versus simvastatin 20-40 mg in patients with coronary heart disease (P=0.07). Adherence was high in both treatment groups but significantly higher in patients treated with simvastatin. Design The Incremental Decrease in End Points through Aggressive Lipid Lowering was a prescription trial with a prospective randomized open label endpoint evaluation. Methods and results Adherence was calculated as exposure time on prescribed drugs divided by total follow-up time until death or end of follow-up and was a potential confounder. Adjusting for categorical adherence below or above 80% by two methods revealed that the relative risk reduction of the primary endpoint was more in the region of 15% (P=0.02) than 11% as found unadjusted. Censoring at the first occurrence of a cardiovascular event rather than at death increased this estimate to 17% (P=0.02). Noncardiovascular mortality was reduced on atorvastatin treatment by 21% (1-37%) after adjustment for adherence, whereas such reduction was not observed for cardiovascular mortality. Conclusion This study found that the difference in adherence between treatment groups may have underestimated the true effect of the treatment differential. Usage of prospective randomized open label endpoint evaluation design should be carefully considered when well-known treatments are compared with rather new ones and especially in segments where patients could be more vulnerable, as in the elderly. Nonadherers in a clinical trial may be at especially high risk of fatal and nonfatal endpoints from various diseases and should be carefully monitored.
|
|
| 19. |
- Holme, Ingar, et al.
(författare)
-
Congestive heart failure is associated with lipoprotein components in statin-treated patients with coronary heart disease Insights from the Incremental Decrease in End points Through Aggressive Lipid Lowering Trial (IDEAL)
- 2009
-
Ingår i: ATHEROSCLEROSIS. - : Elsevier BV. - 0021-9150. ; 205:2, s. 522-527
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Very few, if any, studies have assessed the ability of apolipoproteins to predict new-onset of congestive heart failure (HF) in statin-treated patients with coronary heart disease (CHD). Aims: To employ the Incremental Decrease in End points Through Aggressive Lipid Lowering Trial (IDEAL) study database to assess the association of on-treatment lipoprotein components with prediction of HF events and to compare their predictive value with that of established risk factors such as hypertension and diabetes. Methods: We used Cox regression models to study the relationships between on-treatment levels of apolipoproteins A1 and B to subsequent HE Chi square information value from the log likelihood was used to compare the predictive value of lipoprotein components with established risk factors of HF. Findings: In the IDEAL study, on-treatment apolipoproteins proved to be associated with the occurrence of new-onset HE Variables related to low-density lipoprotein cholesterol (LDL-C) carried less predictive information than those related to high-density lipoprotein cholesterol (HDL-C), and apoA-1 was the single variable most strongly associated with HF. LDL-C was less predictive than both non-HDL-C (total cholesterol minus HDL-C) and apoB. The ratio of apoB to apoA-1 was most strongly related to HF after adjustment for potential confounders, among which diabetes had a stronger correlation with HF than did hypertension. ApoB/apoA-1 carried approximately 2.2 times more of the statistical information value than that of diabetes. Calculation of the net reclassification improvement index revealed that about 3.7% of the patients had to be reclassified into more correct categories of risk once apoB/apoA-1 was added to the adjustment factors. The reduction in risk by intensive lipid-lowering treatment as compared to usual-dose simvastatin was well predicted by the difference in apoB/apoA-1 on-treatment levels. Interpretation: The on-treatment ratio of apoB/apoA-1 was the strongest predictor of HF in CHD patients of both IDEAL treatment arms combined, mostly driven by the strong association with apoA-1, whereas LDL-C and non-HDL-C were less able to predict HF outcome. The predictive information value contained within apoB/apoA-1 was about 2.2 times more than that of diabetes. Between-treatment group differences in HF were to a significant extent explained by on-treatment differences in apoB/apoA-1, mostly through the changes in apoB. We argue therefore, on-treatment lipoprotein components contribute to the overall future risk of HF in statin-treated patients with CHD.
|
|
| 20. |
- Kastelein, John J. P., et al.
(författare)
-
Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment
- 2008
-
Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 117:23, s. 3002-3009
-
Tidskriftsartikel (refereegranskat)abstract
- Background - Low-density lipoprotein (LDL)cholesterol is the principal target of lipid-lowering therapy, but recent evidence has suggested more appropriate targets. We compared the relationships of on-treatment levels of LDL cholesterol, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B, as well as ratios of total/HDL cholesterol, LDL/HDL cholesterol, and apolipoprotein B/A-I, with the occurrence of cardiovascular events in patients receiving statin therapy. Methods and Results - A post hoc analysis was performed that combined data from 2 prospective, randomized clinical trials in which 10 001 ("Treating to New Targets") and 8888 ("Incremental Decrease in End Points through Aggressive Lipid Lowering") patients with established coronary heart disease were assigned to usual-dose or high-dose statin treatment. In models with LDL cholesterol, non-HDL cholesterol and apolipoprotein B were positively associated with cardiovascular outcome, whereas a positive relationship with LDL cholesterol was lost. In a model that contained non-HDL cholesterol and apolipoprotein B, neither was significant owing to collinearity. Total/HDL cholesterol ratio and the apolipoprotein B/A-I ratio in particular were each more closely associated with outcome than any of the individual proatherogenic lipoprotein parameters. Conclusions - In patients receiving statin therapy, on-treatment levels of non-HDL cholesterol and apolipoprotein B were more closely associated with cardiovascular outcome than levels of LDL cholesterol. Inclusion of measurements of the antiatherogenic lipoprotein fraction further strengthened the relationships. These data support the use of non-HDL cholesterol or apolipoprotein B as novel treatment targets for statin therapy. Given the absence of interventions that have been proven to consistently reduce cardiovascular disease risk through raising plasma levels of HDL cholesterol or apolipoprotein A-I, it seems premature to consider the ratio variables as clinically useful.
|
|
| 21. |
- Olsson, Anders, et al.
(författare)
-
LDL cholesterol goals and cardiovascular risk during statin treatment: the IDEAL study
- 2011
-
Ingår i: EUROPEAN JOURNAL OF CARDIOVASCULAR PREVENTION and REHABILITATION. - : Lippincott Williams and Wilkins. - 1741-8267. ; 18:2, s. 262-269
-
Tidskriftsartikel (refereegranskat)abstract
- Aims: We assessed the proportion of patients treated with either simvastatin 20 or 40 mg or atorvastatin 80 mg who achieved low-density lipoprotein cholesterol (LDL-C) goals of 2.5 or 2.0 mmol/l in the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study. We explored how lipoprotein components related to cardiovascular disease (CVD) outcomes in these groups. Methods and results: For subjects who reached on-treatment LDL-C goals, Cox regression models were used to assess the ability of lipoprotein components to predict CVD events. Treatment with simvastatin or atorvastatin resulted in 40 per cent and 80 per cent of patients, respectively, reaching the 2.5 mmol/l goal and 12 per cent and 52 per cent, respectively, reaching the 2.0 mmol/l goal, after 1 year (all p andlt; 0.001 between groups). Adjusting for baseline LDL-C levels, hazard ratio (HR) for those reaching 2.0-2.5 mmol/l LDL-C versus those reaching andlt; 2.0 mmol/l was 1.16 (95% confidence interval [CI], 1.02-1.33, p = 0.023). An increase of the apolipoprotein B/A1 (apoB/A1) ratio by 1 standard deviation in participants who reached 2.0 mmol/l showed a HR for CVD of 1.14 (95% CI, 1.04-1.25, p = 0.004). Conclusion: More CVD patients treated with atorvastatin than simvastatin achieved either LDL-C goal and those reaching the 2.0 mmol/l goal exhibited significantly less CVD than those only reaching 2.5 mmol/l. In those reaching the 2.0 mmol/l goal, the apoB/A1 ratio still bears a relation to CVD outcome. The use of apoB/A1 ratio may provide additional predictive value to that of LDL-C.
|
|
| 22. |
- Pedersen, Terje R, et al.
(författare)
-
Comparison of Atorvastatin 80 mg/day Versus Simvastatin 20 to 40 mg/day on Frequency of Cardiovascular Events Late (Five Years) After Acute Myocardial Infarction (from the Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL] Trial)
- 2010
-
Ingår i: AMERICAN JOURNAL OF CARDIOLOGY. - : Elsevier Science B. V., Amsterdam. - 0002-9149. ; 106:3, s. 354-359
-
Tidskriftsartikel (refereegranskat)abstract
- Previous studies have demonstrated that benefits of intensive statin therapy compared to standard statin therapy begin shortly after an acute event and are continued up to 2 years of follow-up. However, whether efficacy and safety of intensive statin therapy in patients with a recent cardiac event are maintained in longer-term follow-up has not been evaluated. We conducted a post hoc analysis of a subgroup of 999 patients who had a first acute myocardial infarction (MI) andlt;2 months before randomization in a prospective, open-label, blinded end-point evaluation trial of 8,888 patients with a history of MI that compared intensive statin therapy (atorvastatin 80 mg) to standard statin therapy (simvastatin 20 to 40 mg) over approximately 5 years of follow-up. We analyzed the same composite end point used in the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) trial (death, MI, hospitalization for unstable angina, revascularization, and stroke). Rates of the composite end point were 44.7% (n = 226) in the simvastatin group and 37.9% (n = 187) in the atorvastatin group (hazard ratio 0.82, 95% confidence interval 0.67 to 0.99, p = 0.04). Although statistical power was smaller than that of the PROVE IT trial, the relative risk decrease observed at 5 years is consistent with that in the 2-year follow-up in PROVE IT. The 2 treatment regimens were well tolerated. In conclusion, our analysis provides support for the strategy of placing patients with recent MI on intensive statin therapy and maintaining the high dose over the long term, beyond 2 years.
|
|
| 23. |
- Sjouke, Barbara, et al.
(författare)
-
Eprotirome in patients with familial hypercholesterolaemia (the AKKA trial): a randomised, double-blind, placebo-controlled phase 3 study
- 2014
-
Ingår i: LANCET DIABETES and ENDOCRINOLOGY. - : Elsevier: Lancet. - 2213-8587 .- 2213-8595. ; 2:6, s. 455-463
-
Tidskriftsartikel (refereegranskat)abstract
- Background Eprotirome is a liver-selective thyroid hormone receptor agonist that has been shown to lower plasma LDL cholesterol concentrations in previous phase 1 and 2 studies of patients with dyslipidaemia. We aimed to assess the long-term safety and efficacy of 50 mu g and 100 mu g eprotirome in patients with familial hypercholesterolaemia. Methods For this randomised, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial, we enrolled patients between Oct 3, 2011, and Feb 14, 2012, at 53 sites in 11 countries in Europe, Africa, and south Asia. Patients were eligible for enrolment if they were aged 18 years or older, diagnosed with heterozygous familial hypercholesterolaemia, and had not reached target LDL cholesterol concentrations after at least 8 weeks of statin therapy with or without ezetimibe. We used a computer-generated randomisation sequence to allocate patients to one of three groups: 50 mu g eprotirome, 100 mu g eprotirome, or placebo. This trial was planned for 52-76 weeks, with primary efficacy analysis at 12 weeks, but it was prematurely terminated when another study found that eprotirome causes cartilage damage in dogs. Although it was impossible to meet the predefined study outcomes, we analysed changes in the concentrations of LDL cholesterol and other lipids, liver parameters, thyroid hormone concentrations, and adverse effects of treatment with eprotirome versus placebo at 6 weeks of treatment. Analysis was done in all patients who received 6 weeks of treatment. This study is registered with ClinicalTrials.gov, number NCT01410383. Findings We enrolled 236 patients, randomly allocating 80 to receive placebo, 79 to receive 50 mu g eprotirome, and 77 to receive 100 mu g eprotirome. 69 patients reached the 6 week timepoint (23 given placebo, 24 given 50 mu g eprotirome, and 22 given 100 mu g eprotirome). Mean LDL cholesterol concentrations increased by 9% (95% CI -2 to 20) in the placebo group, decreased by 12% (-28 to 4%; p=0.0677 vs placebo) in the 50 mu g eprotirome group, and decreased by 22% (-32 to -13%; p=0.0045 vs placebo) in the 100 mu g eprotirome group. We noted statistically significant increases between both eprotirome groups and placebo in aspartate aminotransferase (AST; pless than0.0001), alanine aminotransferase (ALT; pless than0.0001), conjugated bilirubin (p=0.0006), and gamma-glutamyltranspeptidase (pless than0.0001). Four patients had to discontinue or interrupt study treatment before trial termination due to AST increases between the upper limit of normal (ULN) and six times ULN, and ALT concentrations between three and seven times ULN. Although we detected no changes in serum concentrations of thyroid-stimulating hormone or free tri-iodothyronine, free tetra-iodothyronine decreased by 19% (23 to 16) in the 50 mu g eprotirome group and 27% (30 to 23) in the 100 mu g eprotirome group (pless than0.0001 vs placebo for both groups). Interpretation Our findings show that eprotirome can lower LDL cholesterol concentrations in patients with familial hypercholesterolaemia when added to conventional statin treatment with or without ezetimibe, but that it has the potential to induce liver injury. These findings, along with findings of cartilage damage in dogs, raise serious doubts about selective thyroid hormone mimetics as a therapeutic approach to lower LDL cholesterol concentrations.
|
|
| 24. |
- Strandberg, Timo E, et al.
(författare)
-
Comparative Effect of Atorvastatin (80 mg) Versus Simvastatin (20 to 40 mg) in Preventing Hospitalizations for Heart Failure in Patients With Previous Myocardial Infarction
- 2009
-
Ingår i: AMERICAN JOURNAL OF CARDIOLOGY. - : Elsevier BV. - 0002-9149. ; 103:10, s. 1381-1385
-
Tidskriftsartikel (refereegranskat)abstract
- We investigated whether intensive cholesterol lowering could more effectively prevent heart failure (HF) in secondary prevention. The IDEAL study was a 4.8-year prospective, randomized trial comparing "usual" simvastatin treatment (20 to 40 mg/day, n = 4,449) with high-dose atorvastatin (80 mg/day, n = 4,439) in patients with a history of myocardial infarction (MI). At baseline, 94% of patients (n = 8,351) had no history of HF. During the course of the trial, there were 222 new or recurrent hospitalizations for HF (57 and 165 in those with and without HF at baseline, respectively), 123 (2.8%) in the simvastatin group and 99 (2.2%) in the atorvastatin group (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.62 to 1.05, p = 0.11). After adjustments, atorvastatin 80 mg was associated with a 26% decrease of new HF events compared with simvastatin 20 to 40 mg (HR 0.74, 95% CI 0.57 to 0.97, p = 0.03). Atorvastatin tended to be associated with fewer HF events in those with HF at baseline (n = 537, HR 0.65, 95% CI 0.38 to 1.11, p = 0.11) and those without HF at baseline (n = 8,351, HR 0.80, 95% CI 0.59 to 1.09, p = 0.15). Also, HF without preceding MI (n = 187) was decreased (HR 0.73, 95% CI 0.54 to 0.97, p = 0.03). In conclusion, atorvastatin 80 mg was more efficient than simvastatin 20 to 40 mg in preventing development of HF in patients with previous MI.
|
|
| 25. |
- Tikkanen, Matti J, et al.
(författare)
-
Total Cardiovascular Disease Burden: Comparing Intensive With Moderate Statin Therapy Insights From the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) Trial
- 2009
-
Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 54:25, s. 2353-2357
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives This post-hoc analysis of the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial was designed to assess the comparative treatment efficacy of high-dose atorvastatin and usual-dose simvastatin for the prevention of events subsequent to the first event, using the Wei, Lin, and Weissfeld method. Background Time-to-first-event analysis of data is frequently utilized to provide efficacy outcome information in coronary heart disease prevention trials. However, during the course of such long-term trials, a large number of events occur subsequent to the first event, the analysis of which will be precluded by this approach. Methods The Wei, Lin, and Weissfeld method allows the analysis of repeated occurrence of events of the same type or of entirely different natures. It regards the recurrence times as multivariate event (failure) times, and models the marginal (individual) distribution for each event with the Cox proportional hazards model. Results In the IDEAL trial, compared with patients taking simvastatin 20 to 40 mg daily, patients receiving atorvastatin 80 mg daily had their relative risk of a first cardiovascular event reduced by 17% (p less than 0.0001), of a second by 24% (p less than 0.0001), of a third by 19% (p = 0.035), of a fourth by 24% (p = 0.058), and of a fifth by 28% (p = 0.117). Conclusions Our results indicate that intensive statin therapy continues to be more effective than standard statin therapy, even beyond the first event, and suggest that clinicians should not hesitate to prescribe high-dose statin therapy for patients experiencing multiple recurrent cardiovascular events.
|
|
