| 1. |
- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 2. |
- Pitts, Reynaria, et al.
(författare)
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Aldosterone Does Not Predict Cardiovascular Events Following Acute Coronary Syndrome in Patients Initially Without Heart Failure
- 2017
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Ingår i: Journal of the American Heart Association. - : WILEY-BLACKWELL. - 2047-9980 .- 2047-9980. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Background- Aldosterone may have adverse effects in the myocardium and vasculature. Treatment with an aldosterone antagonist reduces cardiovascular risk in patients with acute myocardial infarction complicated by heart failure (HF) and left ventricular systolic dysfunction. However, most patients with acute coronary syndrome do not have advanced HF. Among such patients, it is unknown whether aldosterone predicts cardiovascular risk. Methods and Results- To address this question, we examined data from the dal-OUTCOMES trial that compared the cholesteryl ester transfer protein inhibitor dalcetrapib with placebo, beginning 4 to 12 weeks after an index acute coronary syndrome. Patients with New York Heart Association class II (with LVEF amp;lt; 40%), III, or IV HF were excluded. Aldosterone was measured at randomization in 4073 patients. The primary outcome was a composite of coronary heart disease death, nonfatal myocardial infarction, stroke, hospitalization for unstable angina, or resuscitated cardiac arrest. Hospitalization for HF was a secondary endpoint. Over a median follow-up of 37 months, the primary outcome occurred in 366 patients (9.0%), and hospitalization for HF occurred in 72 patients (1.8%). There was no association between aldosterone and either the time to first occurrence of a primary outcome (hazard ratio for doubling of aldosterone 0.92, 95% confidence interval 0.78-1.09, P=0.34) or hospitalization for HF (hazard ratio 1.38, 95% CI 0.96-1.99, P=0.08) in Cox regression models adjusted for covariates. Conclusions- In patients with recent acute coronary syndrome but without advanced HF, aldosterone does not predict major cardiovascular events.
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| 3. |
- Schwartz, Gregory G., et al.
(författare)
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Association of Lipoprotein(a) With Risk of Recurrent Ischemic Events Following Acute Coronary Syndrome Analysis of the dal-Outcomes Randomized Clinical Trial
- 2018
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Ingår i: JAMA cardiology. - : AMER MEDICAL ASSOC. - 2380-6583 .- 2380-6591. ; 3:2, s. 164-168
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE It is uncertain whether lipoprotein(a) [Lp(a)], which is associated with incident cardiovascular disease, is an independent risk factor for recurrent cardiovascular events after acute coronary syndrome (ACS). OBJECTIVE To determine the association of Lp(a) concentration measured after ACS with the subsequent risk of ischemic cardiovascular events. DESIGN, SETTING, AND PARTICIPANTS This nested case-cohort analysis was performed as an ad hoc analysis of the dal-Outcomes randomized clinical trial. This trial compared dalcetrapib, the cholesteryl ester transfer protein inhibitor, with placebo in patients with recent ACS and was performed between April 2008 and September 2012 at 935 sites in 27 countries. There were 969 case patients who experienced a primary cardiovascular outcome, and there were 3170 control patients who were event free at the time of a case event and had the same type of index ACS (unstable angina ormyocardial infarction) as that of the respective case patients. Concentration of Lp(a) was measured by immunoturbidimetric assay. Data analysis for this present study was conducted from June 8, 2016, to April 21, 2017. INTERVENTIONS Patients were randomly assigned to receive treatment with dalcetrapib, 600 mg daily, or matching placebo, beginning 4 to 12 weeks after ACS. MAIN OUTCOMES AND MEASURES Death due to coronary heart disease, a major nonfatal coronary event (myocardial infarction, hospitalization for unstable angina, or resuscitated cardiac arrest), or fatal or nonfatal ischemic stroke. RESULTS The mean (SD) age was 63 (10) years for the 969 case patients and 60 (9) years for the 3170 control patients, and both cohorts were composed of predominantly male (770 case patients [79%] and 2558 control patients [81%]; P = .40) and white patients (858 case patients [89%] and 2825 control patients [89%]; P = .62). At baseline, the median (interquartile range) Lp(a) level was 12.3 (4.7-50.9) mg/dL. There was broad application of evidence-based secondary prevention strategies after ACS, including use of statins in 4030 patients (97%). The cumulative distribution of baseline Lp(a) levels did not differ between cases and controls at P = .16. Case-cohort regression analysis showed no association of baseline Lp(a) level with risk of cardiovascular events. For a doubling of Lp(a) concentration, the hazard ratio (case to control) was 1.01 (95% CI, 0.96-1.06; P = .66) after adjustment for 16 baseline variables, including assigned study treatment. CONCLUSIONS AND RELEVANCE For patients with recent ACS who are treated with statins, Lp(a) concentration was not associated with adverse cardiovascular outcomes. These findings call into question whether treatment specifically targeted to reduce Lp(a) levels would thereby lower the risk for ischemic cardiovascular events after ACS.
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| 4. |
- Schwartz, Gregory G., et al.
(författare)
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Dalcetrapib Reduces Risk of New-Onset Diabetes in Patients With Coronary Heart Disease
- 2020
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Ingår i: Diabetes Care. - : AMER DIABETES ASSOC. - 0149-5992 .- 1935-5548. ; 43:5, s. 1077-1084
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE Incident type 2 diabetes is common among patients with recent acute coronary syndrome and is associated with an adverse prognosis. Some data suggest that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes. We compared the effect of treatment with the CETP inhibitor dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome. RESEARCH DESIGN AND METHODS In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib 600 mg daily or placebo, beginning 4-12 weeks after an acute coronary syndrome. Absence of diabetes at baseline was based on medical history, no use of antihyperglycemic medication, and hemoglobin A(1c) and serum glucose levels below diagnostic thresholds. Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, new use of antihyperglycemic medication, hemoglobin A(1c) >= 6.5%, or a combination of at least two measurements of serum glucose >= 7.0 mmol/L (fasting) or >= 11.1 mmol/L (random). RESULTS At baseline, 10,645 patients (67% of the trial cohort) did not have diabetes. During a median follow-up of 30 months, incident diabetes was identified in 403 of 5,326 patients (7.6%) assigned to dalcetrapib and in 516 of 5,319 (9.7%) assigned to placebo, corresponding to absolute risk reduction of 2.1%, hazard ratio of 0.77 (95% CI 0.68-0.88; P < 0.001), and a need to treat 40 patients for 3 years to prevent 1 incident case of diabetes. Considering only those with prediabetes at baseline, the number needed to treat for 3 years to prevent 1 incident case of diabetes was 25. Dalcetrapib also decreased the number of patients who progressed from normoglycemia to prediabetes and increased the number who regressed from diabetes to no diabetes. CONCLUSIONS In patients with a recent acute coronary syndrome, incident diabetes is common and is reduced substantially by treatment with dalcetrapib.
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| 5. |
- Schwartz, Gregory G, et al.
(författare)
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Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome
- 2012
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Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 367:22, s. 2089-2099
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND less thanbrgreater than less thanbrgreater thanIn observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes. less thanbrgreater than less thanbrgreater thanMETHODS less thanbrgreater than less thanbrgreater thanWe randomly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. less thanbrgreater than less thanbrgreater thanRESULTS less thanbrgreater than less thanbrgreater thanAt the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 mg per deciliter (2.0 mmol per liter). Over the course of the trial, HDL cholesterol levels increased from baseline by 4 to 11% in the placebo group and by 31 to 40% in the dalcetrapib group. Dalcetrapib had a minimal effect on LDL cholesterol levels. Patients were followed for a median of 31 months. At a prespecified interim analysis that included 1135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination of the trial for futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P = 0.52) and did not have a significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (Pandlt;0.001 for both comparisons). less thanbrgreater than less thanbrgreater thanCONCLUSIONS less thanbrgreater than less thanbrgreater thanIn patients who had had a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events. (Funded by F. Hoffmann-La Roche; dal-OUTCOMES ClinicalTrials.gov number, NCT00658515.)
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| 6. |
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| 7. |
- Karlson, Björn W., 1953, et al.
(författare)
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Doses of rosuvastatin, atorvastatin and simvastatin that induce equal reductions in LDL-C and non-HDL-C: Results from the VOYAGER meta-analysis
- 2016
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Ingår i: European Journal of Preventive Cardiology. - : Oxford University Press (OUP). - 2047-4873 .- 2047-4881. ; 23:7, s. 744-747
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Tidskriftsartikel (refereegranskat)abstract
- Background Achieving the greatest reduction in atherogenic lipoproteins requires the optimum dose and potency of statin. Using data from the VOYAGER meta-analysis, we determined doses of rosuvastatin, atorvastatin and simvastatin that induce equal reductions in low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C). Methods Least squares mean percentage change in LDL-C and non-HDL-C was calculated using 38,052 patient exposures to rosuvastatin 5-40mg, atorvastatin 10-80mg and simvastatin 10-80mg. Equipotent doses were estimated by linear interpolation between actual adjacent doses. Results Rosuvastatin 5mg reduced LDL-C by 39% and non-HDL-C by 35%. Equivalent reductions in LDL-C required atorvastatin 15mg or simvastatin 39mg. Equivalent reductions in non-HDL-C required atorvastatin 14 mg or simvastatin 42mg. Rosuvastatin 10mg reduced LDL-C by 44% and non-HDL-C by 40%. Equivalent reductions in LDL-C required atorvastatin 29 mg or simvastatin 72mg. Equivalent reductions in non-HDL-C required atorvastatin 27 mg or simvastatin 77mg. Rosuvastatin 20mg reduced LDL-C by 50% and non-HDL-C by 45%. Equivalent reductions in LDL-C and non-HDL-C required atorvastatin 70 mg and atorvastatin 62mg, respectively, and were not achieved with the maximum 80mg dose of simvastatin. Rosuvastatin 40mg reduced LDL-C by 55% and non-HDL-C by 50%. Comparable reductions were not achieved with the maximum 80mg doses of atorvastatin or simvastatin. Conclusions Regarding reductions in LDL-C and non-HDL-C, each rosuvastatin dose is equivalent to doses 3-3.5 times higher for atorvastatin and 7-8 times higher for simvastatin.
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| 8. |
- Karlson, Björn W., 1953, et al.
(författare)
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Variability of low-density lipoprotein cholesterol response with different doses of atorvastatin, rosuvastatin, and simvastatin: results from VOYAGER.
- 2016
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Ingår i: European heart journal. Cardiovascular pharmacotherapy. - : Oxford University Press (OUP). - 2055-6845 .- 2055-6837. ; 2:4, s. 212-7
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Tidskriftsartikel (refereegranskat)abstract
- Patient response to statin treatment is individual and varied. As a consequence, when using a specific-dose approach, as recommended in the 2013 American College of Cardiology/American Heart Association guideline, there will be a range of reductions in the concentration of low-density lipoprotein cholesterol (LDL-C). The aim of this study was to use individual patient data from the VOYAGER meta-analysis to determine the extent of the variability in LDL-C reduction in response to treatment across the recommended doses of different statins.
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| 9. |
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| 10. |
- Salahuddin, Taufiq, et al.
(författare)
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Association of high-density lipoprotein particle concentration with cardiovascular risk following acute coronary syndrome: A case-cohort analysis of the dal-Outcomes trial
- 2020
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Ingår i: American Heart Journal. - : MOSBY-ELSEVIER. - 0002-8703 .- 1097-6744. ; 221, s. 60-66
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Tidskriftsartikel (refereegranskat)abstract
- Background High-density lipoprotein cholesterol (HDL-C) concentration is inversely related to risk of major adverse cardiovascular events (MACE) in epidemiologic studies but is a poorer predictor of MACE in patients with established coronary heart disease. HDL particle concentration (HDLP) has been proposed as a better predictor of risk. We investigated whether HDLP is associated with risk of MACE after acute coronary syndrome (ACS). Methods The dal-Outcomes trial compared the CETP inhibitor dalcetrapib with placebo in patients with recent ACS. In a nested case-cohort analysis, total, large, medium, and small HDLPs were measured by nuclear magnetic resonance spectroscopy at baseline (4-12 weeks after ACS) in 476 cases with MACE and 902 controls. Hazard ratios (HRs; case-control) for 1-SD increment of HDLP or HDL-C at baseline were calculated with and without adjustment for demographic, clinical, laboratory, and treatment variables. Similarly, HRs for MACE were calculated for changes in HDLP or HDL-C from baseline to month 3 of assigned treatment. Results Over median follow-up of 28 months, the risk of MACE was not associated with baseline HDLP (adjusted HR = 0.98, 95% CI = 0.84-1.15, P =.81), any HDLP subclass, or HDL-C. Dalcetrapib increased HDL-C and total, medium, and large HDLP and decreased small HDLP but had no effect on MACE compared with placebo. There were no association of risk of MACE with change in HDLP or HDL-C and no interaction with assigned study treatment. Conclusions Neither baseline HDLP nor the change in HDLP on treatment with dalcetrapib or placebo was associated with risk of MACE after ACS.
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