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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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Fenofibrate increases circulating haematopoietic stem cells in people with diabetic retinopathy: a randomised, placebo-controlled trial.
Bonora, BM, Albiero, M, Morieri, ML, Cappellari, R, Amendolagine, FI, Mazzucato, M, Zambon, A, Iori, E, Avogaro, A, Fadini, GP
Diabetologia. 2021;(10):2334-2344
Abstract
AIM/HYPOTHESIS In two large RCTs, fenofibrate reduced the progression of diabetic retinopathy. We investigated whether fenofibrate increases circulating haematopoietic stem/progenitor cells (HSPCs), which have vascular properties and have been shown to protect from retinopathy. METHODS We conducted a 12 week parallel-group RCT comparing fenofibrate vs placebo. Patients with diabetic retinopathy and without other conditions that would affect HSPCs were enrolled at a tertiary diabetes outpatient clinic and randomised to receive fenofibrate or placebo based on a computer-generated sequence. Patients and study staff assessing the outcomes were blinded to group assignment. The primary endpoint was the change in the levels of circulating HSPCs, defined by expression of the stem cell markers CD34 and/or CD133. Secondary endpoints were the changes in endothelial progenitor cells, lipids, soluble mediators and gene expression. We used historical data on the association between HSPCs and retinopathy outcomes to estimate the effect of fenofibrate on retinopathy progression. RESULTS Forty-two participants with diabetic retinopathy were randomised and 41 completed treatment and were analysed (20 in the placebo group and 21 in the fenofibrate group). Mean age was 57.4 years, diabetes duration was 18.2 years and baseline HbA1c was 60 mmol/mol (7.6%). When compared with placebo, fenofibrate significantly increased levels of HSPCs expressing CD34 and/or CD133. CD34+ HSPCs non-significantly declined in the placebo group (mean ± SD -44.2 ± 31.6 cells/106) and significantly increased in the fenofibrate group (53.8 ± 31.1 cells/106). The placebo-subtracted increase in CD34+ HSPCs from baseline was 30% (99.3 ± 43.3 cells/106; p = 0.027) which, projected onto the relationship between HSPC levels and retinopathy outcomes, yielded an OR of retinopathy progression of 0.67 for fenofibrate vs placebo. Endothelial differentiation of CD34+ cells, estimated by the %KDR (kinase insert domain receptor) expression, was significantly reduced by fenofibrate. Fenofibrate decreased serum triacylglycerols, but the change in triacylglycerols was unrelated to the change in HSPCs. No effect was observed for endothelial progenitor cells, cytokines/chemokines (stromal-cell derived factor-1, vascular endothelial growth factor, monocyte chemoattractant protein-1) and gene expression in peripheral blood mononuclear cells. CONCLUSIONS/INTERPRETATION Fenofibrate increased HSPC levels in participants with diabetic retinopathy and this mechanism may explain why fenofibrate reduced retinopathy progression in previous studies. TRIAL REGISTRATION ClinicalTrials.gov NCT01927315.
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Effect of nebivolol beneficial on lipid profile and glycemic control in comparison with Atenolol in patients with type 2 DM with concomitant hypertension.
Majid, A, Javed, A, Hussain, M, Faisal, Z, Elahi, A, Akhtar, L
Pakistan journal of pharmaceutical sciences. 2021;(5(Supplementary)):1891-1895
Abstract
Blood pressure control in hypertensive patients with metabolic abnormalities is challenging because many antihypertensive drugs adversely affect metabolism. Nebivolol a 3rd generation vasodilatory β-blocker offer neutral or beneficial effects on insulin sensitivity and lipid metabolism. The purpose of this study was to evaluate the effect of nebivolol and atenolol on glycemic control and lipid profile in type 2 diabetes patients with concomitant hypertension. We conducted a 12 weeks double blind randomized clinical trial at Sheik Zayed Hospital Rahim Yar Khan. Patients were randomly divided in to two groups. Patients in group were given tablet nebivolol 5-10mg while patients in group B were given tablet Atenolol 25-50mg/daily for a period of 12 weeks. Pre and post data were analyzed by SPSS 20. After 12 weeks, Both drugs lowered blood pressure significantly i.e. nebivolol (SBP from152±12 to130±14 with p=0.004, DBP from 95±12 to78±8.5 with p=0.002) Atenolol (SBP from148±16.5 to 128±15.5 with p=0.006, DBP from 90±10.5 to 82±12 with p=0.003).Similarly both Nebivolol and Atenolol did not any significant effect on glycemic control and lipid profile at 12 week with in groups. However when comparison was done between two groups, Nebivolol significantly reduced blood sugar (p=0.001), HbA1c (p=0.0032), total Cholesterol (p=0.002), triglycerides (p=0.012), LDL-Cholesterol (p=0.007) and HDL-Cholesterol (p=0.001) as compared to atenolol. In comparison with atenolol, Nebivolol has a beneficial effect on glycemic control and serum lipid profile.
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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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Hypoglycemic and Hypolipemic Effects of a New Lecithin Formulation of Bergamot Polyphenolic Fraction: A Double Blind, Randomized, Placebo- Controlled Study.
Mollace, V, Scicchitano, M, Paone, S, Casale, F, Calandruccio, C, Gliozzi, M, Musolino, V, Carresi, C, Maiuolo, J, Nucera, S, et al
Endocrine, metabolic & immune disorders drug targets. 2019;(2):136-143
Abstract
OBJECTIVE Hyperlipemia represents an independent risk factor in the development of atherosclerosis in patients undergoing type 2 diabetes mellitus (DM). Moreover, the pharmacological treatment of dyslipemia in patients undergoing type 2 DM (e.g. by means of statins), is accompanied by relevant side effects and oral supplementation with natural antioxidants, such as Citrus polyphenols, has recently been suggested to improve cardioprotection in such patients. However, due to the poor gastrointestinal absorption of polyphenols, novel formulations have recently been developed for getting a better bioavailability of polyphenolic rich fractions of citrus species extract rich in polyphenols. METHODS Here, we investigated the effect of standard bergamot polyphenolic fraction (BPF®) as well as of its phytosomal formulation (BPF Phyto), in patients with type 2 DM and hyperlipemia. A randomized, double blind, placebo-controlled study was carried out in 60 patients suffering from type 2 DM and mixed hyperlipemia. Patients were divided into three groups: one receiving placebo, the second receiving standard BPF and the third BPF Phyto. RESULTS In the groups receiving BPF and BPF Phyto, a significant reduction of fasting plasma glucose, serum LDL cholesterol and triglycerides accompanied by increased HDL cholesterol was observed. This effect was associated with significant reduction of small dense atherogenic LDL particles, as detected by means of proton NMR Spectroscopy, thus confirming the hypolipemic and hypoglycemic effect of bergamot extract both when using standard formulation as well as BPF Phyto. No differences were seen in the therapeutic response among groups receiving BPF and BPF Phyto, thus suggesting a substantial bioequivalence in their hypoglycemic and hypolipemic profile. However, when comparing the pharmacokinetic profile of naringin (the major component of BPF) and its metabolites, in patients treated with BPF Phyto, an at least 2,5 fold increase in its absorption was found, confirming in human studies the better profile of BPF Phyto compared to standard BPF. CONCLUSION These data suggest that better absorption and tissue distribution of BPF Phyto formulation represents an innovative approach in supplementation treatments of cardiometabolic disorders.
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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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Abstract
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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Comparing the serum TAG response to high-dose supplementation of either DHA or EPA among individuals with increased cardiovascular risk: the ComparED study.
Allaire, J, Vors, C, Harris, WS, Jackson, KH, Tchernof, A, Couture, P, Lamarche, B
The British journal of nutrition. 2019;(11):1223-1234
Abstract
Studies have shown that the reduction in serum TAG concentrations with long-chain n-3 fatty acid supplementation is highly variable among individuals. The objectives of the present study were to compare the proportions of individuals whose TAG concentrations lowered after high-dose DHA and EPA, and to identify the predictors of response to both modalities. In a double-blind, controlled, crossover study, 154 men and women were randomised to three supplemented phases of 10 weeks each: (1) 2·7 g/d of DHA, (2) 2·7 g/d of EPA and (3) 3 g/d of maize oil, separated by 9-week washouts. As secondary analyses, the mean intra-individual variation in TAG was calculated using the standard deviation from the mean of four off-treatment samples. The response remained within the intra-individual variation (±0·25 mmol/l) in 47 and 57 % of participants after DHA and EPA, respectively. Although there was a greater proportion of participants with a reduction >0·25 mmol/l after DHA than after EPA (45 υ. 32 %; P 0·25 mmol/l after both DHA and EPA had higher non-HDL-cholesterol, TAG and insulin concentrations compared with other responders at baseline (all P < 0·05). In conclusion, supplementation with 2·7 g/d DHA or EPA had no meaningful effect on TAG concentrations in a large proportion of individuals with normal mean TAG concentrations at baseline. Although DHA lowered TAG in a greater proportion of individuals compared with EPA, the magnitude of TAG lowering among them was similar.
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Impact of a cardiovascular disease risk screening result on preventive behaviour in asymptomatic participants of the ROBINSCA trial.
Denissen, SJ, van der Aalst, CM, Vonder, M, Oudkerk, M, de Koning, HJ
European journal of preventive cardiology. 2019;(12):1313-1322
Abstract
INTRODUCTION A teachable moment for preventive behavioural change can occur when asymptomatic individuals receive their cardiovascular disease screening result. This study investigated prevention-seeking behaviour and compliance with preventive treatment of participants of the population-based Risk Or Benefit IN Screening for CArdiovascular disease (ROBINSCA) trial after receiving a screening result. METHODS Asymptomatic Dutch individuals (n = 43,447) were randomly assigned (1:1:1) to screening for cardiovascular disease by either traditional risk assessment (intervention arm A), or determining the amount of coronary artery calcification (intervention arm B), or to usual care (control arm). A random sample (n = 600) of ROBINSCA participants with a screening result (arms A and B) received an online questionnaire (in 2017) to measure the impact of a cardiovascular disease screening result in low and increased (arm A: risk > 10%; arm B: Agatston ≥ 100) risk groups. RESULTS Of all respondents (438/600; 73%) 63.5% were men and the mean age ( ± standard deviation) was 63.8 ± 6.9 years. Individuals with an increased coronary artery calcification score consulted their general practitioner more often compared to increased risk individuals from arm A: 140/149 (94%) and 86/137 (62.8%), respectively (P < 0.001). Current use of blood pressure and cholesterol-lowering drugs was significantly higher in the increased coronary artery calcification score group (108/140; 77.1%), compared to the group with an increased traditional risk (35/80, 43.8%; P < 0.001). Self-reported compliance was high (98.1-100%). CONCLUSION Receiving the screening result might be a teachable moment that can enhance cardiovascular disease prevention-seeking behaviour through consulting a general practitioner and high compliance with preventive treatment. The impact of the screening result was more profound in the increased coronary artery calcification score group. Trial registration number: NTR6471.
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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.