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1.
Incidence of Hospitalization for Heart Failure Relative to Major Atherosclerotic Events in Type 2 Diabetes: A Meta-analysis of Cardiovascular Outcomes Trials.
Sacre, JW, Magliano, DJ, Shaw, JE
Diabetes care. 2020;(10):2614-2623
Abstract
BACKGROUND Emerging evidence points to heart failure as being a common first presentation of cardiovascular (CV) disease in type 2 diabetes. PURPOSE The purpose of this study was to determine whether hospitalization for heart failure (HHF) occurs more or less frequently than major adverse CV events (MACE) in people with type 2 diabetes. DATA SOURCES Placebo arms of CV outcomes trials in type 2 diabetes were included. STUDY SELECTION Sixteen CV outcomes trials were selected, including five dipeptidyl peptidase 4 inhibitor trials, seven glucagon-like peptide 1 receptor agonist trials, and four sodium-glucose cotransporter 2 inhibitor trials. DATA EXTRACTION We extracted incidence rates of HHF, myocardial infarction (MI), stroke, and the composite outcomes of CV death or HHF and MACE (CV death, nonfatal MI, or nonfatal stroke). DATA SYNTHESIS In two trials enriched with people with chronic kidney disease, HHF was more common than both MI and stroke. Among the remaining 14 trials, HHF was less frequent than MI in 13 (93%), with this difference being significant in 8 (57%); however, HHF surpassed stroke in all but 1 study (93%; significant in 7 studies [50%]). Heterogeneity among trials was moderate/high (I 2 >50%) and partly explained by HHF/MI correlating with age and previous MI history (P < 0.05). In seven trials that reported events stratified by presence/absence of preexisting CV disease, ratios of HHF/MI and HHF/stroke were similar between groups. LIMITATIONS Enrichment of trial populations with those at high risk of CV events limits generalizability. CONCLUSIONS Although less frequent than MI, HHF is a common event in type 2 diabetes, both in those with and those without prior CV disease.
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Efficacy of Statin/Ezetimibe for Secondary Prevention of Atherosclerotic Cardiovascular Disease in Asian Populations: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Bhagavathula, AS, Aldhaleei, WA, Al Matrooshi, NO, Rahmani, J
Clinical drug investigation. 2020;(9):809-826
Abstract
BACKGROUND Several clinical trials have investigated the effect of statin/ezetimibe combination therapy on secondary prevention of atherosclerotic cardiovascular disease (ASCVD) in the Asian population. OBJECTIVE This study aimed to summarize study results regarding the effect of statin/ezetimibe combination therapy on lipid parameters and highly sensitive C-reactive protein (HsCRP) biomarkers in ASCVD patients from Asian countries. METHODS We searched the PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar databases for relevant papers published from 2008 to June 2020. We included randomized controlled trials (RCTs) that (1) were conducted in ASCVD patients in Asian countries; (2) examined the effects of statin/ezetimibe combination therapies compared with a control group; and (3) reported sufficient data on lipid parameters and HsCRP biomarkers. The results were reported as weighted mean differences (WMDs) with 95% confidence intervals (CI) using random-effects models. Funnel plots and Egger's regression test were used to assess publication bias. RESULTS Twenty-four RCTs were reviewed and 20 were included in the meta-analysis. A total of 4344 participants were included (n = 2197 in the intervention group and n = 2147 in the control group), and the intervention durations ranged from 6 weeks to 3.6 years. Ezetimibe coadministered with statin therapy, compared with control treatment, significantly reduced low-density lipoprotein cholesterol (LDL-C; n = 20 studies) [WMD - 0.39 mmol/L, 95% CI - 0.73 to - 0.05; p < 0.001], triglycerides (TG; n = 18 studies) [WMD - 0.23 mmol/L, 95% CI - 0.33 to - 0.13; p < 0.001], and total cholesterol (TC; n = 17 studies) [WMD - 0.31 mmol/L, 95% CI - 0.45 to - 0.17; p < 0.001). Although the effect of statin/ezetimibe combinations on high-density lipoprotein cholesterol (HDL-C; n = 17 studies) [WMD 0.02 mmol/L, 95% CI - 0.05 to 0.09; p < 0.001) was very minimal and no effect was observed on HsCRP levels (n = 11 studies). CONCLUSIONS Our study found that statin/ezetimibe combinations reduced LDL-C, TC, and TG levels but had minimal effects on HDL-C and no effect HsCRP biomarkers in ASCVD patients. The statin/ezetimibe therapy enabled a more effective reduction in LDL-C levels; however, the duration of the treatment was suboptimal.
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PCSK9 inhibitors and cardiovascular outcomes.
Steffens, D, Bramlage, P, Scheeff, C, Kasner, M, Hassanein, A, Friebel, J, Rauch-Kröhnert, U
Expert opinion on biological therapy. 2020;(1):35-47
Abstract
Introduction: Dyslipidemia, particularly elevated low-density lipoprotein cholesterol (LDL-C), is a key risk factor for atherosclerotic cardiovascular disease (ASCVD), and lipid-lowering drugs are beneficial for the primary and secondary prevention of cardiovascular (CV) disease. While statins are clear first-line drugs, new drug developments such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to improve cardiovascular outcomes when added to statins. Evolocumab reduced the risk of cardiovascular events in patients with ASCVD when added to maximally tolerated statin therapy (± ezetimibe), and recent data from the ODYSSEY OUTCOMES trial indicate that alirocumab added to maximally tolerated statin therapy (± other lipid-lowering drugs) reduces the risk of cardiovascular events in patients with a recent acute coronary syndrome. In this article the authors review the available data on the effect of PCSK9 inhibitors on cardiovascular outcomes.Areas covered: This article reviews the available data on the effect of PCSK9 inhibitors on CV outcomes. Relevant papers were identified from a search of PubMed/Medline and the Cochrane Central Register of Controlled Trials (CENTRAL).Expert opinion: The authors conclude that PCSK9 inhibitors provide substantial and durable reductions in LDL-C levels and improve cardiovascular outcomes.
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Glucose-lowering drugs or strategies, atherosclerotic cardiovascular events, and heart failure in people with or at risk of type 2 diabetes: an updated systematic review and meta-analysis of randomised cardiovascular outcome trials.
Ghosh-Swaby, OR, Goodman, SG, Leiter, LA, Cheng, A, Connelly, KA, Fitchett, D, Jüni, P, Farkouh, ME, Udell, JA
The lancet. Diabetes & endocrinology. 2020;(5):418-435
Abstract
BACKGROUND In our 2015 systematic review and meta-analysis of cardiovascular outcome trials for glucose-lowering drugs or strategies in people with or at risk of type 2 diabetes, we reported a modest reduction in atherosclerotic cardiovascular events and an increased risk of heart failure, but with heterogeneous effects by drug or intervention type. In view of the completion of many large cardiovascular outcome trials since our previous analysis, including trials of novel drugs that have shown beneficial effects on cardiovascular outcomes, we aimed to update our analysis to incorporate these findings. METHODS We did an updated systematic review and meta-analysis of large cardiovascular outcome trials of glucose-lowering drugs or strategies in people with or at risk of type 2 diabetes. We searched Ovid MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials databases for reports of trials published from Nov 15, 2013 to Nov 20, 2019. We included randomised controlled trials with a minimum of 1000 adults (aged ≥19 years) with or at risk of type 2 diabetes, with major adverse cardiovascular events (MACE) as an outcome, and with follow-up of at least 12 months. We excluded trials with patients enrolled with an acute cardiovascular event. The main outcomes of interest were MACE (generally defined as a composite of cardiovascular death, myocardial infarction, or stroke) and heart failure. We calculated pooled risk ratios (RRs) and 95% CIs with inverse-variance random-effects models, did meta-regression to analyse treatment effects per difference in bodyweight achieved, and explored results stratified by baseline subgroups. FINDINGS Our updated search yielded 30 eligible trials (n=225 305). The mean age of participants was 63·0 years (SD 8·4) and mean duration of diabetes was 9·4 years (6·6). After a mean follow-up of 3·8 years (1·8), 23 016 (10·2%) participants had MACE and 8169 (3·6%) had a heart failure event. Glucose-lowering drugs or strategies lowered the risk of MACE compared with standard care or placebo (RR 0·92, 95% CI 0·89-0·95, p<0·0001), with no overall effect on the risk of heart failure (0·98, 0·90-1·08, p=0·71). However, across drug classes or strategies, the magnitude and directionality of RR for heart failure varied (pinteraction<0·0001), with meta-regression showing that a decrease in bodyweight of 1 kg was associated with a 5·9% (3·9-8·0) relative decrease in the risk of heart failure (p<0·0001). Among trials that assessed drug classes or strategies associated with weight loss (intensive lifestyle changes, GLP-1 receptor agonists, or SGLT2 inhibitors), the risk reduction for MACE was consistent among participants with (0·87, 0·83-0·92) and without (0·92, 0·83-1·02) established cardiovascular disease at baseline (pinteraction=0·33). For heart failure, the RR for drug classes or strategies associated with weight loss was consistent among participants with (0·80, 0·73-0·89) and without (0·84, 0·74-0·95) cardiovascular disease at baseline (pinteraction=0·63). INTERPRETATION Glucose-lowering drugs or strategies overall reduced the risk of fatal and non-fatal atherosclerotic events. The effect on heart failure was neutral overall but varied substantially by intervention type, with interventions associated with weight loss showing a beneficial effect. The cardiovascular and heart failure benefits of interventions associated with weight loss might extend to patients without established cardiovascular disease. FUNDING None.
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Meta-Analysis Evaluating Calcium Channel Blockers and the Risk of Peripheral Arterial Disease in Patients With Hypertension.
Shetty, S, Malik, AH, Feringa, H, El Accaoui, R, Girotra, S
The American journal of cardiology. 2020;(6):907-915
Abstract
Clinical studies have shown that calcium channel blockers (CCB) can mitigate the progression of atherosclerosis. Their role in the primary prevention of peripheral artery disease (PAD) is unclear. We conducted a meta-analysis of randomized control trials (RCT) to compare the impact of CCB on the incidence of PAD in patients with hypertension. A comprehensive review of the literature was performed in PubMed and Cochrane registry. Studies were included if they were RCT and had outcome data on PAD with a follow-up duration of at least 6 months. CCB formed the intervention group, whereas the control group was constituted by either placebo or active treatment with any of the other antihypertensive medications. A random-effects meta-analysis was performed, and we report odds ratio as a measure of treatment effect. Our search identified 934 trials, of which 7 RCTs with 71,971 patients fulfilled the inclusion criteria. The mean duration of follow-up was 3.8 years. In patients receiving CCB, PAD events occurred in 547 out of 27,502 patients (2%) compared with 1,263 out of 42,659 patients in the control group (3%). Based on the random-effect model, the odds for development of PAD in hypertensive patients treated with CCB compared with the control group was 0.70 (95% confidence interval of 0.58 to 0.86, p = 0.0005). In conclusion, this meta-analysis of RCTs of hypertensive patients, we found that treatment with CCB was strongly associated with a decrease in the PAD compared with other antihypertensive agents or placebo.
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Impediments to clinical application of exercise interventions in the treatment of cardiometabolic disease.
Bosomworth, NJ
Canadian family physician Medecin de famille canadien. 2019;(3):164-170
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Association Between Circulating Oxidized LDL and Atherosclerotic Cardiovascular Disease: A Meta-analysis of Observational Studies.
Gao, S, Zhao, D, Wang, M, Zhao, F, Han, X, Qi, Y, Liu, J
The Canadian journal of cardiology. 2017;(12):1624-1632
Abstract
BACKGROUND Although basic research has suggested that oxidized low-density lipoprotein (ox-LDL) is involved in the pathogenesis of atherosclerosis, population observational studies have yielded conflicting results about the association between circulating ox-LDL and atherosclerotic cardiovascular disease (ASCVD). Therefore, we performed a systematic review and meta-analysis of currently available observational studies to verify the association between circulating ox-LDL and ASCVD. METHODS We systematically searched PubMed and the Cochrane Library from their inception to March 27, 2017, for nested case-control studies, case-cohort studies, and prospective cohort studies on the relationship between ox-LDL and ASCVD. Studies that did not assess the hazard ratio, relative risk, or odds ratio of ox-LDL or did not adjust for other risk factors, or those without examination of ox-LDL before collection of ASCVD occurrences were excluded. The summarized effect size was combined using fixed effect models. Subgroup analyses were performed on the basis of study quality, study design, definition of ASCVD events, effect size types, types of ox-LDL assay, ox-LDL contrast level, and whether low-density lipoprotein cholesterol was adjusted in a multivariate model. RESULTS A total of 12 included studies consisted of 3 nested case-control studies, 1 case-cohort study, 5 hospital-based cohort studies, and 3 community-based cohort studies. The summary effect size of increased circulating ox-LDL was 1.79 (95% confidence interval, 1.56-2.05) for ASCVD. Similar associations were shown in all subgroups. CONCLUSIONS Our findings indicate that increased levels of circulating ox-LDL are associated with clinical ASCVD events. Further well designed community-based cohort studies or intervention studies are needed to confirm our findings.
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Moderate alcohol consumption and atherosclerosis : Meta-analysis of effects on lipids and inflammation.
Huang, Y, Li, Y, Zheng, S, Yang, X, Wang, T, Zeng, J
Wiener klinische Wochenschrift. 2017;(21-22):835-843
Abstract
OBJECTIVE Alcohol consumption plays an important role in the risk of major cardiovascular diseases. We conducted a meta-analysis to summarize the association between moderate alcohol consumption and atherosclerosis. DESIGN In this study four databases and reference lists of retrieved articles were searched to identify eligible studies. A meta-analysis was carried out of all interventional studies that assessed the effects of moderate alcohol consumption on concentrations of low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, apolipoprotein A I, interleukin 6, plasminogen activator inhibitor 1, fibrinogen, and other biomarkers previously found to be associated with risk of atherosclerosis. RESULTS A total of 31 studies met the eligibility criteria. In response to moderate alcohol consumption, low density lipoprotein cholesterol decreased by 0.08 mmol/l (P = 0.05), and high density lipoprotein cholesterol increased by 0.08 mmol/l (P < 0.00001), whereas total cholesterol and triglyceride remained the same. Moreover, interleukin 6 decreased by 0.43 pg/ml (P = 0.03), whereas C‑reactive protein and tumor necrosis factor a remained the same. Several hemostatic factors and adiponectin were modestly affected by alcohol consumption. CONCLUSION Moderate alcohol consumption is causally related to lower risk of atherosclerosis through changes in lipid profiles and inflammation.
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Association of Matrix Gla protein gene (rs1800801, rs1800802, rs4236) polymorphism with vascular calcification and atherosclerotic disease: a meta-analysis.
Sheng, K, Zhang, P, Lin, W, Cheng, J, Li, J, Chen, J
Scientific reports. 2017;(1):8713
Abstract
Association between the MGP gene rs1800801, rs1800802, rs4236 polymorphisms and vascular calcification and atherosclerotic disease was inconsistent. To clarify precise association, we performed this meta-analysis. Medline, Embase and China Knowledge Resource Integrated Database were systematically searched through December 2016. A total of 23 case-control studies, consisting of 5280 cases and 5773 controls, were included. The overall results suggested that the -7A polymorphism was associated with an increased risk for vascular calcification and atherosclerotic disease in the recessive model (OR = 1.50, 95% CI 1.01-2.24, P = 0.045). Subgroup analyses of Caucasians showed significant associations in the allelic model, recessive model, and homozygote model: allelic model (OR = 1.19, 95% CI 1.06-1.34, P = 0.004), recessive model (OR = 1.60, 95% CI 1.26-2.03, P < 0.001), homozygote model (OR = 1.83, 95% CI 1.18-2.81, P = 0.006). Subgroup analysis of the Asian population did not demonstrate any significant associations in any of the genetic models. No significant association was found in any genetic model amongst the rs1800802 and rs4236 polymorphisms. The findings of this meta-analysis indicate that the MGP gene rs1800801 polymorphism is significantly associated with vascular calcification and atherosclerotic disease, especially in the Caucasian population.
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Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration.
Willeit, P, Thompson, SG, Agewall, S, Bergström, G, Bickel, H, Catapano, AL, Chien, KL, de Groot, E, Empana, JP, Etgen, T, et al
European journal of preventive cardiology. 2016;(2):194-205
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Abstract
BACKGROUND Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population. METHODS Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses. RESULTS Mean baseline CCA-IMT amounted to 0.74 mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082 mm for high-sensitivity C-reactive protein (p < 0.001); 0.0072 mm for fibrinogen (p < 0.001); and 0.0025 mm for leucocyte count (p = 0.033). 'Inflammatory load', defined as the number of elevated inflammatory markers (i.e. in upper two quintiles), showed a positive linear association with baseline CCA-IMT (p < 0.001). Longitudinal associations of baseline inflammatory markers and changes therein with CCA-IMT progression were null or at most weak. Participants with the highest 'inflammatory load' had a greater CCA-IMT progression (p = 0.015). CONCLUSION Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for 'inflammatory load' suggest important combined effects of the three inflammatory markers on early atherosclerosis.