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Protective lipid-lowering variants in healthy older individuals without coronary heart disease.
Lacaze, P, Riaz, M, Sebra, R, Hooper, AJ, Pang, J, Tiller, J, Polekhina, G, Tonkin, A, Reid, C, Zoungas, S, et al
Open heart. 2021;(2)
Abstract
OBJECTIVE Genetic variants that disrupt the function of the PCSK9 (proprotein convertase subtilisin kexin type 9) and APOB (apolipoprotein B)genes result in lower serum low-density lipoprotein cholesterol (LDL-C) levels and subsequently confer protection against coronary heart disease (CHD). The objective of this study was to measure the prevalence and selective advantage of such variants among healthy older individuals without a history of CHD. METHODS We performed targeted sequencing of the PCSK9 and APOB genes in 13 131 healthy individuals without CHD aged 70 years or older enrolled into the ASPirin in Reducing Events in the Elderly trial. We detected variants in the PCSK9 and APOB genes with predicted loss-of-function. We associated variant carrier status with serum LDL-C and total cholesterol (TC) levels at the time of study enrolment, adjusting for statin use. RESULTS We detected 22 different rare PCSK9/APOB candidate variants with putative lipid-lowering effect, carried by 104 participants (carrier rate 1 in 126). Serum LDL-C and TC concentrations for rare PCSK9/APOB variant carriers were consistently lower than non-carriers. Rare variant carrier status was associated with 19.4 mg/dL (14.6%) lower LDL-C, compared with non-carriers (p≤0.001, adjusted for statin use). Statin prescriptions were less prevalent in rare variant carriers (16%) than non-carriers (35%). The more common PCSK9 R46L variant (rs11591147-T) was associated with 15.5 mg/dL (11.8%) lower LDL-C in heterozygotes, and 25.2 mg/dL (19.2%) lower LDL-C in homozygotes (both p≤0.001). CONCLUSIONS Lipid-lowering genetic variants are carried by healthy older individuals and contribute to CHD-free survival. TRIAL REGISTRATION NUMBER NCT01038583.
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Risk Factors Control and Early Recurrent Cerebral Infarction in Patients with Symptomatic Intracranial Atherosclerotic Disease.
Del Brutto, VJ, Liebeskind, DS, Romano, JG, Campo-Bustillo, I, Cotsonis, G, Nizam, A, Prabhakaran, S, ,
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2021;(9):105914
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BACKGROUND The risk of early recurrent cerebral infarction (RCI) is high in patients with symptomatic intracranial atherosclerotic disease (IAD). We sought to determine the relationship between risk factor control and early RCI risk among patients with symptomatic IAD. METHODS We analyzed participants with symptomatic IAD in the multi-center prospective observational MYRIAD study. Risk factor control was assessed at 6-8-week follow-up. Optimal risk factor control was defined by target systolic blood pressure, being non-smoker, target physical activity, and antiplatelet and antilipidemic therapy compliance. Age-adjusted associations were calculated between risk factor control and RCI determined by MRI-evident new infarcts in the territory of the stenotic vessel at 6-8 weeks from the index event. RESULTS Among 82 participants with clinical and brain MRI information available 6-8 weeks after the index event (mean age 63.5 ±12.5 years, 62.2% men), RCI occurred in 21 (25.6%) cases. At 6-8-week follow-up, 37.8% had target systolic blood pressure, 92.7% were non-smokers, 51.2% had target physical activity, and 98.8% and 86.6% were compliant with antiplatelet and antilipidemic therapy, respectively. Optimal risk factor control increased from 4.9% at baseline to 19.5% at 6-8-week follow-up (p=0.01). None of the participants with optimal risk factor control at follow-up had RCI (0% vs. 31.8%, p<0.01). CONCLUSIONS Only one-fifth of MYRIAD participants had optimal risk factor control during early follow-up. Approximately half and two-thirds had physical inactivity and uncontrolled systolic blood pressure, respectively. These risk factors may represent important therapeutic targets to prevent early RCI in patients with symptomatic IAD.
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Lipid Management and 2-Year Clinical Outcomes in Japanese Patients with Acute Coronary Syndrome: EXPLORE-J.
Nakamura, M, Ako, J, Arai, H, Hirayama, A, Nohara, A, Murakami, Y, Ozaki, A, Harada-Shiba, M
Journal of atherosclerosis and thrombosis. 2021;(12):1307-1322
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AIM: The prevalence of atherosclerotic cardiovascular (CV) disease has risen in Japan due to increasing metabolic risk factors, including dyslipidemia. A positive linear correlation between low-density lipoprotein cholesterol (LDL-C) levels, incidence of CV events, and preventive effects of lipid-lowering therapy (LLT) is well established; however, data in Japan are limited. This analysis evaluated current lipid management practices and risk of recurrent CV events in Japanese post-acute coronary syndrome (ACS) patients. METHODS EXPLORE-J is a multicenter, 2-year observational study of hospitalized ACS patients in Japan. RESULTS At 2-year follow-up (n=1944, mean age 66 years, 80.3% male), the cumulative incidence of major adverse cardiovascular events (MACE; death associated with myocardial infarction/cerebrovascular accident [CVA] and other CV death, non-fatal ACS, and non-fatal CVA requiring hospitalization during the observation period) was 6.2%; respective incidences of CV death, non-fatal ACS, and CVA were 0.7%, 4.5%, and 1.7%. Statin, intensive statin, and ezetimibe were prescribed for 93.6%, 8.2%, and 3.9% at visit (V)1 (Day[D]1+14), and 92.3%, 10.5%, and 11.6% of patients at V5 (D730±30 days), respectively. Mean LDL-C was reduced from first post-ACS measurement (121.3 mg/dL) to V5 (79.8 mg/dL). A limited number of patients achieved LDL-C <70 mg/dL from V1-V5 (14.4%-34.6%); those with a greater LDL-C reduction by V1 had a lower probability of MACE, indicating the benefits of early LDL-C reduction post ACS. CONCLUSIONS Guideline-recommended LDL-C target achievement post ACS in Japan is suboptimal, suggesting the need for LLT intensification. Additional analyses by risk stratification of the study population and the benefits of lipid management are planned.
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Dipeptidyl peptidase-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels in patients with type 2 diabetes: A randomized controlled trial.
Onoue, T, Goto, M, Wada, E, Furukawa, M, Okuji, T, Okada, N, Kobayashi, T, Iwama, S, Sugiyama, M, Tsunekawa, T, et al
PloS one. 2020;(1):e0228004
Abstract
Type 2 diabetes and dyslipidemia are diseases that collectively increase the risk of patients developing cardiovascular complications. Several incretin-based drugs are reported to improve lipid metabolism, and one of these medications, anagliptin, is a dipeptidyl peptidase-4 (DPP-4) inhibitor that has been shown to decrease serum triglyceride and low-density lipoproteins cholesterol. This study aimed to conduct an investigation into the effects of anagliptin on serum lipid profiles. This multicenter, open-label, randomized (1:1), parallel group study was designed to evaluate the effects of anagliptin on serum lipid profiles (triglycerides, lipoproteins, apolipoproteins, and cholesterol fractions). The study involved 24 patients with type 2 diabetes at two participating hospitals for a period of 24 weeks. Patients were randomly assigned to the anagliptin (n = 12) or control (n = 12) groups. Patients in the anagliptin group were treated with 200 mg of the drug twice daily. Patients in the control group did not receive anagliptin, but continued with their previous treatment schedules. Lipid metabolism was examined under fasting conditions at baseline and 24 weeks. Patients treated with anagliptin for 24 weeks exhibited significantly reduced levels of serum apolipoprotein B-48, a marker for lipid transport from the intestine, compared with the control group patients (P < 0.05). After 24 weeks of treatment, serum adiponectin levels were significantly raised, whereas glycated hemoglobin (HbA1c) levels were significantly lower compared with the baseline in the anagliptin group (P < 0.05), but not in the control group. This study showed that the DPP-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels, suggesting that this drug may have beneficial effects on lipid metabolism possibly mediated by the inhibition of intestinal lipid transport.
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Efficacy and safety of coenzyme A versus fenofibrate in patients with hyperlipidemia: a multicenter, double-blind, double-mimic, randomized clinical trial.
Chen, YQ, Zhao, SP, Ye, HJ
Current medical research and opinion. 2020;(6):941-945
Abstract
Background: We investigated the lipid-lowering efficacy and safety of coenzyme A (CoA) versus fenofibrate in Chinese patients with moderate dyslipidemia.Methods: A total of 417 subjects (aged 18-75 years) diagnosed with moderate dyslipidemia (triglyceride 2.3-6.5 mmol/L) from 13 large cardiovascular centers in China were recruited and randomly divided into a fenofibrate group (n = 207), which received 200 mg of fenofibrate orally once daily, and a CoA group (n = 210), which received 400 mg of CoA orally once a day. Blood lipoproteins, liver and renal function, creatine kinase, and blood glucose were measured at baseline, and after 4 and 8 weeks of treatment.Results: The baseline triglyceride (TG) level in the fenofibrate group and the CoA group was 3.39 ± 0.99 mmol/L and 3.60 ± 1.11 mmol/L, respectively. After treatment for 4 and 8 weeks with fenofibrate, TG was reduced by 31.62% and 33.13%. In the CoA group, TG was reduced by 17.29% and 23.80%. Compared with baseline, total cholesterol (TC) was significantly decreased in both groups after either 4 or 8 weeks of treatment (p < .05). CoA increased high-density lipoprotein cholesterol (HDL-C) after 4 weeks of treatment, whereas it had no significant effect on HDL-C after 8 weeks of treatment. Low-density lipoprotein cholesterol (LDL-C) was not modified in either group. The incidence of side effects was significantly lower in the CoA group compared with the fenofibrate group (p < .05).Conclusions: Compared with fenofibrate, CoA has less effect on reducing plasma TG levels in subjects with moderate dyslipidemia. However, it has fewer adverse effects.
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Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial.
Ouchi, Y, Sasaki, J, Arai, H, Yokote, K, Harada, K, Katayama, Y, Urabe, T, Uchida, Y, Hayashi, M, Yokota, N, et al
Circulation. 2019;(12):992-1003
Abstract
BACKGROUND Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C) lowering therapy in older individuals, aged ≥75 years, is insufficient. This trial tested whether LDL-C-lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. METHODS This multicenter, prospective, randomized, open-label, blinded end-point evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥75 years, with elevated LDL-C without history of coronary artery disease. Patients, who all received dietary counseling, were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke. RESULTS Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50-0.86; P=0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37-0.98; P=0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18-0.79; P=0.007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups. CONCLUSIONS LDL-C-lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution. Clinical Registration: URL: https://www.umin.ac.jp. Unique identifier: UMIN000001988.
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Suboptimal lipid levels in clinical practice among Portuguese adults with dyslipidemia under lipid-lowering therapy: Data from the DISGEN-LIPID study.
da Silva, PM, Aguiar, C, Morais, J, ,
Revista portuguesa de cardiologia. 2019;(8):559-569
Abstract
INTRODUCTION Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in Portugal. Hypercholesterolemia has a causal role in atherosclerotic CVD. Guidelines recommend that cardiovascular (CV) risk reduction should be individualized and treatment goals identified. Low-density lipoprotein cholesterol (LDL-C) is the primary treatment target. METHODS DISGEN-LIPID was a cross-sectional observational study conducted in 24 centers in Portugal in dyslipidemic patients aged ≥40 years, on lipid-lowering therapy (LLT) for at least three months and with an available lipid profile in the previous six months. RESULTS A total of 368 patients were analyzed: 48.9% men and 51.1% women (93.9% postmenopausal), of whom 73% had a SCORE of high or very high CV risk. One quarter had a family history of premature CVD; 31% had diabetes; 26% coronary heart disease; 9.5% cerebrovascular disease; and 4.1% peripheral arterial disease. Mean baseline lipid values were total cholesterol (TC) 189 mg/dl, LDL-C 116 mg/dl, high-density lipoprotein cholesterol (HDL-C) 53.5 mg/dl, and triglycerides (TG) 135 mg/dl. Women had higher TC (p<0.001), LDL-C (non-significant) and HDL-C (p<0.001), and lower TG (p=0.002); 57% of men and 63% of women had LDL-C>100 mg/dl (p=0.28), and 58% of men and 47% of women had LDL-C>70 mg/dl (p=0.933). CONCLUSION These observational data show that, despite their high-risk profile, more than half of patients under LLT, both men and women, did not achieve the recommended target levels for LDL-C, and a large proportion also had abnormal HDL-C and/or TG. This is a renewed opportunity to improve clinical practice in CV prevention.
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Relation between baseline LDL-cholesterol and cardiovascular outcomes in high cardiovascular risk hypertensive patients: A post-hoc SPRINT data analysis.
Nguyen, LS, Procopi, N, Salem, JE, Squara, P, Funck-Brentano, C
International journal of cardiology. 2019;:159-161
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BACKGROUND Patients at increased cardiovascular (CV) risk, noticeably hypertensive patients, have multiple CV risk factors which may be treatment targets. LDL-cholesterol is one of such targets. Using the SPRINT cohort, studying the cardiovascular outcomes of hypertensive patients at increased CV risk, this post-hoc study aimed to assess the association of LDL-C with CV outcomes. METHODS Clinical outcomes were those defined in SPRINT a composite of various CV outcomes, all-cause mortality, and CV mortality. Association between LDL-C and the primary outcome was analyzed using survival regression adjusted on confounding factors (age, sex, body-mass index, active smoking status, eGFR-estimated kidney function, history of CV disease, Framingham risk score, SPRINT treatment arm (intensive or control), baseline high-density-lipoprotein-bound cholesterol, and co-treatments by aspirin and statins). RESULTS LDL-C was not associated with the primary outcome in the overall cohort (n = 9631). Among patients in secondary prevention (i.e. with a previous history of CV disease) (n = 1562), LDL-C was marginally associated with the incidence of the primary outcome (adjusted hazard-ratio 1.005 (95% CI = 1.002-1.009), p = 0.005 (per 1 mg/dl increase)) however, discrimination was poor with a ROC AUC of 0.54, p = 0.087. There was no association between LDL-C and the primary outcome in other subgroup analyses (those under statin or not, and those in primary prevention). CONCLUSION This post-hoc analysis of SPRINT indicates that LDL-C levels do not influence cardiovascular events over a period of 3 years in a large cohort of hypertensive patients at increased risk of cardiovascular events but without previous history of clinical cardiovascular disease other than stroke.
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Effects of Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) on Atherogenic Lipid/Lipoprotein, Apolipoprotein, and Inflammatory Parameters in Patients With Elevated High-Sensitivity C-Reactive Protein (from the ANCHOR Study).
Miller, M, Ballantyne, CM, Bays, HE, Granowitz, C, Doyle, RT, Juliano, RA, Philip, S
The American journal of cardiology. 2019;(5):696-701
Abstract
Icosapent ethyl is pure prescription eicosapentaenoic acid approved at 4 g/day as an adjunct to diet to reduce triglycerides (TG) in adults with TG ≥500 mg/dl. Elevated high-sensitivity C-reactive protein (hsCRP) is associated with increased cardiovascular risk. The 12-week ANCHOR study randomized 702 statin-treated patients at increased cardiovascular risk with TG 200 to 499 mg/dl despite low-density lipoprotein cholesterol (LDL-C) control (40 to 99 mg/dl). This post hoc analysis assessed 246 ANCHOR patients with baseline hsCRP ≥ 2.0 mg/L randomized to icosapent ethyl 4 g/day (n = 126; approved dose) or placebo (n = 120). Without increasing LDL-C, icosapent ethyl significantly reduced median TG (-20%; p < 0.0001), non-high-density lipoprotein cholesterol (-12.3%; p < 0.0001), total cholesterol (-11.1%; p < 0.0001), high-density lipoprotein cholesterol (-5.2%; p = 0.0042), very LDL-C (-21.0%; p < 0.0001), very low-density lipoprotein TG (-22.9%; p < 0.0001), remnant lipoprotein cholesterol (-23.0%; p = 0.0125), apolipoprotein B (-7.4%; p = 0.0021), apolipoprotein C-III (-16%; p < 0.0001), oxidized LDL (-13.7%; p = 0.0020), lipoprotein-associated phospholipase A2 (-19.6%; p < 0.0001), and hsCRP (-17.9%; p = 0.0213) versus placebo, while interleukin-6 and intercellular adhesion molecule-1 were not significantly changed. Eicosapentaenoic acid increased with icosapent ethyl 4 g/day +637% in plasma and +632% in red blood cells versus placebo (both p < 0.0001). Icosapent ethyl exhibited a safety profile similar to placebo. In conclusion, in statin-treated patients with hsCRP ≥ 2.0 mg/L and TG 200 to 499 mg/dl at baseline, icosapent ethyl 4 g/day significantly and safely reduced TG and other atherogenic and inflammatory parameters without increasing LDL-C versus placebo.
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Effect of lipid-lowering treatment in cardiovascular disease prevalence in familial hypercholesterolemia.
Perez-Calahorra, S, Laclaustra, M, Marco-Benedí, V, Lamiquiz-Moneo, I, Pedro-Botet, J, Plana, N, Sanchez-Hernandez, RM, Amor, AJ, Almagro, F, Fuentes, F, et al
Atherosclerosis. 2019;:245-252
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BACKGROUND AND AIMS The impact on heterozygous familial hypercholesterolemia (HeFH) health led by high-intensity lipid-lowering therapy (HILLT) is unknown, and the question remains if there is still an unacceptably high residual risk to justify treatment with new lipid-lowering drugs. METHODS This observational, retrospective, multicenter, national study in Spain, whose information was obtained from a national dyslipemia registry, was designed to establish the current prevalence of cardiovascular disease (CVD) in HeFH and to define the impact of HILLT on CVD in this population. Odds were estimated using several logistic regression models with progressive adjustment. RESULTS 1958 HeFH, mean age 49.3 ± 14.3 years, were included in the analysis. At inclusion in the registry, 295 patients (15.1%) had suffered CVD and 164 (55.6%) had suffered the first event before the onset lipid-lowering treatment. Exposition to treatment associated more than ten times lower odds for CVD than in subjects naïve to treatment (OR 0.085, 95% CI 0.063-0.114, p < 0.001). A first CVD event after a mean treatment period of 9.1 ± 7.2 years occurred in 131 out of 1615 (8.1%) HeFH subjects, and 115 (87.8%) of them were on HILLT. CONCLUSIONS Current prevalence of CVD among HeFH is one third of that reported before the statins era. Early initiation and prolonged lipid-lowering treatment was associated with a reduction in CVD. New cases of CVD, in spite of HILLT, appeared mostly among patients accumulating risk factors and probably they may be considered for further lipid-lowering drugs.