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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.
Schmidt, AF, Holmes, MV, Preiss, D, Swerdlow, DI, Denaxas, S, Fatemifar, G, Faraway, R, Finan, C, Valentine, D, Fairhurst-Hunter, Z, et al
BMC cardiovascular disorders. 2019;(1):240
Abstract
BACKGROUND We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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Impact of blood pressure lowering, cholesterol lowering and their combination in Asians and non-Asians in those without cardiovascular disease: an analysis of the HOPE 3 study.
Pais, P, Jung, H, Dans, A, Zhu, J, Liu, L, Kamath, D, Bosch, J, Lonn, E, Yusuf, S
European journal of preventive cardiology. 2019;(7):681-697
Abstract
BACKGROUND AND DESIGN There are limited data on the effects of blood pressure and cholesterol lowering in Asians at intermediate risk and no cardiovascular disease. We report an analysis of the effects of blood pressure and cholesterol lowering in Asians enrolled in the Heart Outcomes Prevention Evaluation 3 (HOPE 3) trial. METHODS We randomly assigned 6241 Asians and 6464 non-Asians at intermediate risk without cardiovascular disease to candesartan 16 mg/hydrochlorothiazide 12.5 mg or placebo and rosuvastatin 10 mg or placebo. The first co-primary outcome was a composite of cardiovascular disease death, myocardial infarction and stroke. The second co-primary outcome additionally included heart failure, cardiac arrest and revascularisation. Median follow-up was 5.6 years. RESULTS Reduction in systolic blood pressure was less among Asians (4.3 vs. 7.7 mmHg for non-Asians, P < 0.0001) mainly due to a lesser effect in Chinese (2.1 mmHg) than in other Asians (7.3 mmHg), reduction in the latter being similar to non-Asians. The effect on the composite outcomes was similar, with no significant benefits from blood pressure lowering for either Asians (Chinese or non-Chinese) or non-Asians. Rosuvastatin reduced low-density lipoprotein cholesterol to a lesser degree in Asians (0.49 mmol/L (-19.1 mg/dL) compared with non-Asians 0.95 mmol/L (-36.7 mg/dL), Pinteraction < 0.0004). Yet both groups had similar reductions in the two co-primary outcomes. There was no increase in permanent medication discontinuation due to muscle-related symptoms in either group. There was an excess in new diabetes in non-Asians (4.70% rosuvastatin, 3.52% placebo, P = 0.025) but not in Asians (3.02% rosuvastatin, 4.04% placebo, P = 0.0342), Pinteraction = 0021. CONCLUSIONS Candesartan/hydrochlorothiazide had fewer effects in reducing blood pressure in Chinese and rosuvastatin reduced low-density lipoprotein cholesterol to a lesser extent in Asians compared with non-Asians. There was no overall reduction in clinical events with lowering blood pressure in either Asians or non-Asians, whereas there were clear and consistent benefits with lipid lowering in both. Despite extensive analyses, we have no obvious explanation for the observed findings. Future studies need to include larger numbers of individuals from different regions of the world to ensure that the results of trials are applicable globally.
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Establishing a familial hypercholesterolaemia register - The first year.
Tilney, M
Atherosclerosis. Supplements. 2019;:24-27
Abstract
BACKGROUND AND AIMS Familial hypercholesterolemia (FH) is an autosomal dominant condition raising the risk of premature cardiovascular disease up to twentyfold.[1] [2] It is under-diagnosed and undertreated, in spite of availability of effective treatment. Registers are recommended to assist in the recognition and improvement of the condition since treatment reduces morbidity and mortality. Disease registers enable longitudinal review and the application of continuous quality improvement methodology. The aims of this paper are to describe the process of setting up a new FH register in Malta based on phenotype, the preliminary results achieved, the barriers encountered, how these were overcome, and future plans for development. METHODS The registry was established as an observational clinical study designed for a small healthcare system with limited resources. Effective process design requires attention to standards, capacity, outcome measurement and feedback, which have been incorporated. RESULTS 43 individuals have been registered applying Dutch Lipid Clinic Network standards, including 9 Definite, 16 Probable and 18 Possible FH. Cascade testing has identified three younger, and one older FH individuals; amenable risk factors and target outcomes are available for feedback and action. Barriers included insufficient infrastructure, limited stakeholder involvement, time limitations impacting clinical care and data collection, poor recognition, awareness and referral, and limited cascade testing. Overcoming these required persistence, reorganizing clinical work, with some assistance from clinic nurses, forward planning to involve patients and raising FH awareness through presentations to various audiences. CONCLUSIONS During this year the register was established and is functional: awareness is being raised. Future steps will target process improvement for effectiveness and sustainability.
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Effect of Alirocumab on Coronary Atheroma Volume in Japanese Patients With Acute Coronary Syndrome - The ODYSSEY J-IVUS Trial.
Ako, J, Hibi, K, Tsujita, K, Hiro, T, Morino, Y, Kozuma, K, Shinke, T, Otake, H, Uno, K, Louie, MJ, et al
Circulation journal : official journal of the Japanese Circulation Society. 2019;(10):2025-2033
Abstract
BACKGROUND In patients with acute coronary syndrome (ACS), alirocumab reduced the risk of recurring ischemic events. ODYSSEY J-IVUS assessed the effect of alirocumab on coronary atheroma volume in Japanese patients recently hospitalized with ACS and hypercholesterolemia, using intravascular ultrasound imaging analysis.Methods and Results:Patients (n=206) who at index ACS diagnosis either had low-density lipoprotein cholesterol (LDL-C) ≥2.59 mmol/L (≥100 mg/dL) despite stable statin therapy, or were not on statins with LDL-C levels above target after statin initiation, were randomized (1:1) to alirocumab (75 mg every 2 weeks [Q2 W]/up to 150 mg Q2 W), or standard of care (SoC; atorvastatin ≥10 mg/day or rosuvastatin ≥5 mg/day) for 36 weeks. The primary efficacy endpoint (week [W] 36 mean [standard error] percent change in normalized total atheroma volume [TAV] from baseline) was -3.1 (1.0)% with SoC vs. -4.8 (1.0)% with alirocumab (between-group difference: -1.6 [1.4]; P=0.23). W36 absolute change from baseline in percent atheroma volume was -1.3 (0.4)% (SoC) and -1.4 (0.4)% (alirocumab; nominal P=0.79). At W36, LDL-C was reduced from baseline by 13.4% (SoC) vs. 63.9% (alirocumab; nominal P<0.0001). In total, 61.8% (SoC) and 75.7% (alirocumab) of patients reported treatment-emergency adverse events. CONCLUSIONS In Japanese patients with ACS and hypercholesterolemia inadequately controlled despite statin therapy, from baseline to W36, a numerically greater percent reduction in normalized TAV was observed with alirocumab vs. SoC, which did not reach statistical significance.
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The Effect of Ramadan Fasting on Body Composition and Metabolic Syndrome in Apparently Healthy Men.
Al-Barha, NS, Aljaloud, KS
American journal of men's health. 2019;(1):1557988318816925
Abstract
There are few studies investigating the role of Ramadan fasting on body composition and the characteristics of metabolic syndrome, especially in hot environments. The main aim of the study was to investigate the effect of Ramadan fasting on body composition and the characteristics of metabolic syndrome in apparently healthy men. In a randomized design, 44 college students aged 27.6 ± 5.8 years were selected to participate in the present study. Lifestyle was assessed by a developed questionnaire, body composition was measured using a bioelectrical impedance analyzer, and blood parameters were evaluated by taking a vein blood sample (10 ml) after fasting 10 hr. All measurements were taken 2-3 days before the month of Ramadan, at the end of Week 2 and end of Week 3, and 6 weeks later. The results identified no significant changes in any of the body composition parameters before, during, or after the month of Ramadan. The only significant change in blood parameters was recorded as a positive reduction in low-density lipoprotein (LDL) during the month of Ramadan, compared to before and after Ramadan. No major changes in metabolic syndrome factors were seen except in fasting blood glucose and systolic blood pressure as both factors were slightly but significantly elevated during the month of Ramadan and even after Ramadan, though both of them were within normal levels. This study concludes that Ramadan fasting could be one of the factors that reduce LDL. More studies are needed to clarify the role of Ramadan fasting on different populations such as obese and diabetic patients.
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Dose-dependent effects of lifestyle interventions on blood lipid levels: Results from the PREMIER trial.
Dudum, R, Juraschek, SP, Appel, LJ
Patient education and counseling. 2019;(10):1882-1891
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Abstract
OBJECTIVE To assess the effects of comprehensive lifestyle modification on low-density lipoprotein cholesterol (LDL-C) levels and whether greater participation in counseling sessions was associated with greater LDL-C reductions. METHODS Multicenter trial of Pre- or Stage 1 hypertensive adults randomized to: (1)Advice alone, (2)'Established' lifestyle intervention implementing physical activity, sodium reduction, and weight loss, if overweight, or (3)'Established + DASH' lifestyle intervention with DASH diet counseling. Both intervention groups received behavioral counseling. We used generalized estimating equations to model the intervention's effects on lipid outcomes. Analyses of number of sessions and lipids were adjusted for demographics and medical history. RESULTS Among 756 participants (mean age 49.7, 63.2% women, 34.7% black), both lifestyle interventions reduced LDL-C, triglycerides, and total cholesterol (TC) at six months. Compared to the 'Advice' arm, net mean lipid changes in the Established group were: LDL-C of -5.6 mg/dL (p=0.001) and TC of -7.3 mg/dL (p<0.001). Similarly, changes in the 'Established + DASH' group were: LDL-C of -4.0 mg/dL (p=0.03) and TC of -5.7 mg/dL (p=0.006). In dose-response analyses, for every 10-session increase, LDL-C changed by -6.2 mg/dL (p=0.003). CONCLUSIONS Comprehensive lifestyle modification lowers LDL-C with greater benefit among persons who attend more counseling sessions. PRACTICE IMPLICATIONS Patient engagement is a critical aspect of effective lifestyle interventions.
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Impact of Lipid-Lowering Therapy on Mortality According to the Baseline Non-HDL Cholesterol Level: A Meta-Analysis.
Masson, W, Lobo, M, Siniawski, D, Molinero, G, Huerín, M, Nogueira, JP
High blood pressure & cardiovascular prevention : the official journal of the Italian Society of Hypertension. 2019;(4):263-272
Abstract
INTRODUCTION Previous report showed that more intensive lipid-lowering therapy was associated with less mortality when baseline LDL-C levels were > 100 mg/dL. Non-HDL-C is a better predictor of cardiovascular risk than simpler LDL-C. AIM: The objective of this meta-analysis was to define the impact of lipid-lowering therapy on the reduction of total and cardiovascular mortality by different baseline levels of non-HDL-C. METHODS We performed a meta-analysis including randomized, controlled clinical trials of lipid-lowering therapy, reporting mortality with a minimum of 6 months of follow-up, searching in PubMed/Medline, EMBASE and Cochrane Clinical Trials databases. The random-effects model and meta-regression were performed. RESULTS Twenty nine trials of lipid-lowering drugs, including 233,027 patients, were considered eligible for the analyses. According to the baseline non-HDL-C level, the results on cardiovascular mortality were: (1) ≥ 190 mg/dL: OR 0.63 (95% CI 0.53-0.76); (2) 160-189 mg/dL: OR 0.82 (95% CI 0.75-0.89); (3) 130-159 mg/dL: OR 0.71 (95% CI 0.52-0.98); (4) < 130 mg/dL: OR 0.95 (95% CI 0.87-1.05). When evaluating mortality from any cause, the results were the following: (1) ≥ 190 mg/dL: OR 0.70 (95% CI 0.61-0.82); (2) 160-189 mg/dL: OR 0.91 (95% CI 0.83-0.98); (3) 130-159 mg/dL; OR 0.88 (95% CI 0.77-1.00); (4) < 130 mg/dL: OR 0.98 (95% CI 0.91-1.06). The meta-regression analysis showed a significant association between baseline non-HDL-C and mortality. CONCLUSIONS In these meta-analyses, lipid-lowering therapy was associated with reduction in the risk of all-cause and cardiovascular mortality when baseline non-HDL-C levels were above than 130 mg/dL.
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Rare Protein-Truncating Variants in APOB, Lower Low-Density Lipoprotein Cholesterol, and Protection Against Coronary Heart Disease.
Peloso, GM, Nomura, A, Khera, AV, Chaffin, M, Won, HH, Ardissino, D, Danesh, J, Schunkert, H, Wilson, JG, Samani, N, et al
Circulation. Genomic and precision medicine. 2019;(5):e002376
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Abstract
Background Familial hypobetalipoproteinemia is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding APOB (apolipoprotein B), the major protein component of LDL (low-density lipoprotein) and triglyceride-rich lipoprotein particles. Whether heterozygous APOB deficiency is associated with decreased risk for coronary heart disease (CHD) is uncertain. We combined family-based and large scale gene-sequencing to characterize the association of rare PTVs in APOB with circulating LDL-C (LDL cholesterol), triglycerides, and risk for CHD. Methods We sequenced the APOB gene in 29 Japanese hypobetalipoproteinemia families, as well as 57 973 individuals derived from 12 CHD case-control studies-18 442 with early-onset CHD and 39 531 controls. We defined PTVs as variants that lead to a premature stop, disrupt canonical splice-sites, or lead to insertions/deletions that shift reading frame. We tested the association of rare APOB PTV carrier status with blood lipid levels and CHD. Results Among 29 familial hypobetalipoproteinemia families, 8 families harbored APOB PTVs. Carrying 1 APOB PTV was associated with 55 mg/dL lower LDL-C ( P=3×10-5) and 53% lower triglyceride level ( P=2×10-4). Among 12 case-control studies, an APOB PTV was present in 0.038% of CHD cases as compared to 0.092% of controls. APOB PTV carrier status was associated with a 43 mg/dL lower LDL-C ( P=2×10-7), a 30% decrease in triglycerides ( P=5×10-4), and a 72% lower risk for CHD (odds ratio, 0.28; 95% CI, 0.12-0.64; P=0.002). Conclusions Rare PTV mutations in APOB which are associated with lower LDL-C and reduced triglycerides also confer protection against CHD.
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Is There a Need to Revise Goals in the Management of Dyslipidemias?
Sinning, D, Landmesser, U
Current cardiology reports. 2019;(6):51
Abstract
PURPOSE OF REVIEW Current guidelines on the management of patients with dyslipidemias recommend specific risk-dependent low-density lipoprotein cholesterol (LDL-C) treatment goals. Recently, several randomized clinical trials have investigated further lowering of LDL-C in addition to statin therapy using novel therapeutic approaches and examined their effects on cardiovascular (CV) risk. This review summarizes newly available data on efficacy and safety of lowering LDL-C beyond statin therapy and below current treatment targets. RECENT FINDINGS In patients at very high risk for CV events, a significant residual risk remains when failing to achieve significant LDL-C reduction on maximally tolerated statin therapy alone. Further lowering of LDL-C, even beyond current treatment targets, has been shown to be safe and was associated with a further reduced CV risk reduction. The relative risk reduction per change in LDL-C levels has been observed to be consistent even in patient populations achieving extremely low levels of LDL-C. In patients at very high CV risk, further lowering of LDL-C beyond statin therapy and present treatment targets has been observed to further reduce CV risk, which may be foremost relevant for patients at a particular high absolute CV risk, e.g., for patients with progressive and/or very extensive coronary disease.
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Cholesterol-Lowering Agents.
Rosenson, RS, Hegele, RA, Koenig, W
Circulation research. 2019;(3):364-385
Abstract
Loss-of-function variants in PCSK9 (proprotein convertase subtilisin-kexin type 9) are associated with lower lifetime risk of atherosclerotic cardiovascular disease) events. Confirmation of these genetic observations in large, prospective clinical trials in participants with atherosclerotic cardiovascular disease has provided guidance on risk stratification and enhanced our knowledge on hitherto unresolved and contentious issues concerning the efficacy and safety of markedly lowering LDL-C (low-density lipoprotein cholesterol). PCSK9 has a broad repertoire of molecular effects. Furthermore, clinical trials with PCSK9 inhibitors demonstrate that reductions in atherosclerotic cardiovascular disease events are more effective in patients with recent myocardial infarction, multiple myocardial infarctions, multivessel coronary artery disease, and lower extremity arterial disease. The potent LDL-C lowering efficacy of PCSK9 inhibitors provides the opportunity for more aggressive LDL-lowering strategies in high-risk patients with atherosclerotic cardiovascular disease and supports the notion that there is no lower limit for LDL-C. Aggressive LDL-C lowering with fully human PCSK9 monoclonal antibodies has been associated by a safety profile superior to that of other classes of LDL-lowering agents. These clinical trials provide evidence that LDL lowering with PCSK9 inhibitors is an effective therapy for lowering cardiovascular events in high-risk patients with LDL-C levels ≥70 mg/dL on maximally tolerated oral therapies, including statins and ezetimibe.