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Efficacy and Safety of PCSK9 Inhibition With Evolocumab in Reducing Cardiovascular Events in Patients With Metabolic Syndrome Receiving Statin Therapy: Secondary Analysis From the FOURIER Randomized Clinical Trial.
Deedwania, P, Murphy, SA, Scheen, A, Badariene, J, Pineda, AL, Honarpour, N, Keech, AC, Sever, PS, Pedersen, TR, Sabatine, MS, et al
JAMA cardiology. 2021;(2):139-147
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Abstract
IMPORTANCE The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER randomized clinical trial. Patients with metabolic syndrome (MetS) are at increased cardiovascular risk. OBJECTIVE To investigate outcomes with evolocumab in patients with and without MetS. DESIGN, SETTING, AND PARTICIPANTS The FOURIER trial randomized patients worldwide with stable atherosclerotic cardiovascular disease receiving statin to evolocumab vs placebo with follow-up for a median of 2.2 years. Data were collected February 2013 to November 2016. For this prespecified analysis, patients with the requisite data were stratified based on the National Cholesterol Education Program Adult Treatment Panel III MetS criteria; in secondary analyses, patients were further substratified by diabetes at baseline. Analysis was intention to treat. Analysis began March 2018 and ended April 2020. INTERVENTIONS Patients were randomized to evolocumab or placebo. MAIN OUTCOMES AND MEASURES The primary end point was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary end point was cardiovascular death, myocardial infarction, or stroke. RESULTS Of 27 342 patients (mean [SD] age, 63 [9] years; 20 623 men [75.4%]) included in this analysis, 16 361 (59.8%) with baseline MetS were, when compared with patients without MetS, at higher risk of cardiovascular events (adjusted hazard ratio [95% CI], 1.31 [1.18-1.46]; P < .001 for the primary and 1.38 [1.20-1.57]; P < .001 for the key secondary end point). Evolocumab reduced low-density lipoprotein cholesterol similarly in patients with MetS (median [interquartile range], 92 [79-109] mg/dL vs 30 [19-48] mg/dL; P < .001) and without MetS (median [interquartile range], 92 [81-108] mg/dL vs 29 [18-44] mg/dl; P < .001). For the primary end point, the hazard ratios (95% CI) with evolocumab vs placebo were 0.83 (0.76-0.91) and 0.89 (0.79-1.01) in patients with and without MetS (P for interaction = .39). For the key secondary end point, the corresponding hazard ratios (95% CIs) were 0.76 (0.68-0.86) and 0.86 (0.74-1.01) (P for interaction = .23), respectively. Evolocumab did not increase the risk of new-onset diabetes or other major safety outcomes including worsening glycemic control, compared with placebo in patients with MetS. CONCLUSIONS AND RELEVANCE Patients with atherosclerotic cardiovascular disease and MetS have substantial residual risk of cardiovascular events despite statin therapy. Evolocumab significantly reduced low-density lipoprotein cholesterol and cardiovascular risk in patients with MetS without increasing new-onset diabetes, worsening glycemic control, or other major safety events. These data suggest the addition of evolocumab to statin therapy in patients with atherosclerotic cardiovascular disease and MetS is safe and efficacious to reduce residual cardiovascular risk. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01764633.
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The Prognostic Significance of Body Mass Index and Metabolic Parameter Variabilities in Predialysis CKD: A Nationwide Observational Cohort Study.
Park, S, Cho, S, Lee, S, Kim, Y, Park, S, Kim, YC, Han, SS, Lee, H, Lee, JP, Joo, KW, et al
Journal of the American Society of Nephrology : JASN. 2021;(10):2595-2612
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Abstract
BACKGROUND The association between variabilities in body mass index (BMI) or metabolic parameters and prognosis of patients with CKD has rarely been studied. METHODS In this retrospective observational study on the basis of South Korea's national health screening database, we identified individuals who received ≥3 health screenings, including those with persistent predialysis CKD (eGFR <60 ml/min per 1.73 m2 or dipstick albuminuria ≥1). The study exposure was variability in BMI or metabolic parameters until baseline assessment, calculated as the variation independent of the mean and stratified into quartiles (with Q4 the highest quartile and Q1 the lowest). We used Cox regression adjusted for various clinical characteristics to analyze risks of all-cause mortality and incident myocardial infarction, stroke, and KRT. RESULTS The study included 84,636 patients with predialysis CKD. Comparing Q4 versus Q1, higher BMI variability was significantly associated with higher risks of all-cause mortality (hazard ratio [HR], 1.66; 95% confidence interval [95% CI], 1.53 to 1.81), P [for trend] <0.001), KRT (HR, 1.20; 95% CI, 1.09 to 1.33; P<0.001), myocardial infarction (HR, 1.19; 95% CI, 1.05 to 1.36, P=0.003), and stroke (HR, 1.19; 95% CI, 1.07 to 1.33, P=0.01). The results were similar in the subgroups divided according to positive or negative trends in BMI during the exposure assessment period. Variabilities in certain metabolic syndrome components (e.g., fasting blood glucose) also were significantly associated with prognosis of patients with predialysis CKD. Those with a higher number of metabolic syndrome components with high variability had a worse prognosis. CONCLUSIONS Higher variabilities in BMI and certain metabolic syndrome components are significantly associated with a worse prognosis in patients with predialysis CKD.
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Performance of Guideline Recommendations for Prevention of Myocardial Infarction in Young Adults.
Zeitouni, M, Nanna, MG, Sun, JL, Chiswell, K, Peterson, ED, Navar, AM
Journal of the American College of Cardiology. 2020;(6):653-664
Abstract
BACKGROUND The 2018 cholesterol guidelines of the American Heart Association and the American College of Cardiology (AHA/ACC) changed 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor (statin) eligibility criteria for primary prevention to include multiple risk enhancers and novel intensive lipid-lowering therapies for secondary prevention. OBJECTIVES This study sought to determine how guideline changes affected identification for preventive therapy in young adults with premature myocardial infarction (MI). METHODS The study identified adults presenting with first MI at Duke University Medical Center in Durham, North Carolina. Statin therapy eligibility was determined using the 2013 ACC/AHA and 2018 AHA/ACC guidelines criteria. The study also determined potential eligibility for intensive lipid-lowering therapies (very high risk) under the 2018 AHA/ACC guidelines, by assessing the composite of all-cause death, recurrent MI, or stroke rates in adults considered "very high risk" versus not. RESULTS Among 6,639 patients with MI, 41% were <55 years of age ("younger"), 35% were 55 to 65 years of age ("middle-aged"), and 24% were 66 to 75 years of age ("older"). Younger adults were more frequently smokers (52% vs. 38% vs. 22%, respectively) and obese (42% vs. 34% vs. 31%, respectively), with metabolic syndrome (21% vs. 19% vs. 17%, respectively) and higher low-density lipoprotein cholesterol (117 vs. 107 vs. 103 mg/dl, respectively) (p trend <0.01 for all). Pre-MI, fewer younger adults met guideline indications for 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor (statin) therapy than middle-aged and older adults. The 2018 guideline identified fewer younger adults eligible for statin therapy at the time of their MI than the 2013 guideline (46.4% vs. 56.7%; p < 0.01). Younger patients less frequently met very high-risk criteria for intensive secondary prevention lipid-lowering therapy (28.3% vs. 40.0% vs. 81.4%, respectively; p < 0.01). Over a median 8 years of follow-up, very high-risk criteria were associated with increased risk of major adverse cardiovascular events in individuals <55 years of age (hazard ratio: 2.09; 95% confidence interval: 1.82 to 2.41; p < 0.001), as was the case in older age groups (p interaction = 0.54). CONCLUSIONS Most younger patients with premature MI are not identified as statin candidates before their event on the basis of the 2018 guidelines, and most patients with premature MI are not recommended for intensive post-MI lipid management.
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The preventive effects of lifestyle intervention on the occurrence of diabetes mellitus and acute myocardial infarction in metabolic syndrome.
Kim, D, Yoon, SJ, Lim, DS, Gong, YH, Ko, S, Lee, YH, Lee, HS, Park, MS, Kim, KH, Kim, YA
Public health. 2016;:178-182
Abstract
OBJECTIVES Metabolic syndrome (MS), as a precursor of diabetes mellitus (DM) and cardiovascular disease, is increasing steadily worldwide. We examined the preventive effects of lifestyle intervention on the occurrence of DM and acute myocardial infarction (AMI) in MS. STUDY DESIGN Observational study on disease occurrence after lifestyle intervention. METHODS The lifestyle intervention was administered to subjects with MS participating in a metropolitan lifestyle intervention program for 1 year. The same numbers of non-participating age- and sex-matched subjects with MS were randomly extracted from national health examination data. After intervention or examination, new occurrences of hypertension, DM, and AMI were identified through the national health insurance claims data during 1 year. For DM and AMI, multivariate logistic regression analysis for the factors affecting each disease was performed. RESULTS In the intervention group and the control group (14,918 in each group), the occurrence of hypertension was 555 (6.07%) and 751 (8.33%), the occurrence of DM was 324 (2.55%) and 488 (3.89%), the occurrence of dyslipidemia was 321 (2.59%) and 373 (2.72%), and the occurrence of AMI was 13 (0.09%) and 26 (0.17%), respectively. In multivariate logistic regression analysis, adjusted odds ratios for intervention were 0.752 (95% confidence interval [CI]: 0.644-0.879) and 0.499 (95% CI: 0.251-0.992) for DM and AMI, respectively, indicating that lifestyle intervention has a preventive effect. CONCLUSIONS Lifestyle intervention in MS has preventive effects on the occurrence of DM and AMI, and long-term follow-up is needed to evaluate these preventive effects in more detail.
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N-acetylcysteine administration prevents nonthyroidal illness syndrome in patients with acute myocardial infarction: a randomized clinical trial.
Vidart, J, Wajner, SM, Leite, RS, Manica, A, Schaan, BD, Larsen, PR, Maia, AL
The Journal of clinical endocrinology and metabolism. 2014;(12):4537-45
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CONTEXT The acute phase of the nonthyroidal illness syndrome (NTIS) is characterized by low T3 and high rT3 levels, affecting up to 75% of critically ill patients. Oxidative stress has been implicated as a causative factor of the disturbed peripheral thyroid hormone metabolism. OBJECTIVE The objective of the study was to investigate whether N-acetylcysteine (NAC), a potent intracellular antioxidant, can prevent NTIS in patients with acute myocardial infarction. DESIGN This was a randomized, multicenter clinical trial. SETTINGS Consecutive patients admitted to the emergency and intensive care units of two tertiary hospitals in southern Brazil were recruited. Patients and intervention included 67 patients were randomized to receive NAC or placebo during 48 hours. Baseline characteristics and blood samples for thyroid hormones and oxidative parameters were collected. MAIN OUTCOME Variation of serum T3 and rT3 levels was measured. RESULTS Baseline characteristics were similar between groups (all P > .05). T3 levels decreased in the placebo group at 12 hours of follow-up (P = .002) but not in NAC-treated patients (P = .10). Baseline rT3 levels were elevated in both groups and decreased over the initial 48 hours in the NAC-treated patients (P = .003) but not in the control group (P = .75). The free T4 and TSH levels were virtually identical between the groups throughout the study period (P > .05). Measurement of total antioxidant status and total carbonyl content demonstrated that oxidative balance was deranged in acute myocardial infarction patients, whereas NAC corrected these alterations (P < .001). CONCLUSIONS NAC administration prevents the derangement in thyroid hormone concentrations commonly occurring in the acute phase of acute myocardial infarction, indicating that oxidative stress is involved in the NTIS pathophysiology.
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Do apolipoproteins improve coronary risk prediction in subjects with metabolic syndrome? Insights from the North Italian Brianza cohort study.
Gianfagna, F, Veronesi, G, Guasti, L, Chambless, LE, Brambilla, P, Corrao, G, Mancia, G, Cesana, G, Ferrario, MM
Atherosclerosis. 2014;(1):175-81
Abstract
OBJECTIVE We assessed predictive abilities and clinical utility of CVD risk algorithms including ApoB and ApoAI among non-diabetic subjects with metabolic syndrome (MetS). METHODS Three independent population-based cohorts (3677 35-74 years old) were enrolled in Northern Italy, adopting standardized MONICA procedures. Through Cox models, we assessed the associations between lipid measures and first coronary events, as well as the changes in discrimination and reclassification (NRI) when standard lipids or apolipoproteins were added to the CVD risk algorithm including non-lipids risk factors. Finally, the best models including lipids or apolipoproteins were compared. RESULTS During the 14.5 years median follow-up time, 164 coronary events were validated. All measures showed statistically significant associations with the endpoint, while in the MetS subgroup HDL-C and ApoAI (men, HR = 1.59; 95%CI: 0.96-2.65) were not associated. Models including HDL-C plus TC and ApoB plus ApoAI for lipids and apolipoproteins, respectively, showed the best predictive values. When ApoB plus ApoAI replaced TC plus HDL-C, NRI values improved in subjects with MetS (13.8; CI95%: -5.1,53.1), significantly in those previously classified at intermediate risk (44.5; CI95% 13.8,129.6). In this subgroup, 5.5% of subjects was moved in the high (40.0% of expected events) and 17.0% in the low risk class (none had an event at 10 years). CONCLUSIONS ApoB and ApoAI could improve coronary risk prediction when used as second level biomarkers in non-diabetic subjects with MetS classified at intermediate risk. The absence of cases moved downward suggests the gain in avoiding treatments in non-cases and favor the use of apolipoproteins for risk assessment.
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Quality of life and related factors in a cohort of plaque-type psoriasis patients in La Coruña, Spain.
Fernández-Torres, RM, Pita-Fernández, S, Fonseca, E
International journal of dermatology. 2014;(11):e507-11
Abstract
BACKGROUND Psoriasis can significantly affect the physical, psychological, and social aspects of a patient's life. Many studies have evaluated the effects of psoriasis on quality of life (QoL), but results in many cases are contradictory. OBJECTIVES This study was conducted to assess the relationships between the characteristics of psoriasis (cutaneous severity, arthropathy, treatment) and comorbidities with QoL and to determine which factors have a major influence. METHODS We assessed demographic data, the severity of cutaneous involvement, psoriasis treatment, presence of arthropathy, psoriasis duration, smoking status, alcohol intake, and the presence of comorbidities. Concomitant diseases were evaluated using the Charlson Comorbidity Index and the National Cholesterol Education Program Adult Treatment Panel III (ATP-III) criteria for metabolic syndrome. Quality of life was assessed using the Dermatology Life Quality Index (DLQI). RESULTS Multivariate analysis showed that factors associated with QoL impairment included gender (women experienced greater impact: odds ratio [OR] 2.85, 95% confidence interval [CI] 1.48-5.49; P = 0.002); psoriasis duration (patients with longer durations of psoriasis and psoriasis treatment experienced less impairment: OR 0.96, 95% CI 0.94-0.99; P = 0.004); and treatment type (impact was lower in patients receiving biologic drugs than in those using topical treatment [OR 3.15, 95% CI 1.50-6.62; P = 0.002] and in those using biologics compared with those using conventional systemic treatment [OR 2.23, 95% CI 0.98-5.05; P = 0.053]). Psoriasis severity measured according to scores on the Psoriasis Area and Severity Index (PASI) and body surface area affected was not related to QoL impairment. Comorbidities were associated with impaired QoL in the univariate analysis but not after adjusting for other covariates. CONCLUSIONS Factors associated with greater impairment of QoL were gender, psoriasis duration, and type of treatment. Patients receiving systemic and biologic therapies reported better QoL.
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Evidence for a beneficial effect of glucose-insulin-potassium in patients with acute coronary syndromes: Did the IMMEDIATE trial solve an unanswered question?
Mellbin, L, Rydén, L
Expert review of cardiovascular therapy. 2012;(9):1097-9
Abstract
Evaulation of: Selker HP, Beshansky JR, Sheehan PR et al. Out-of-hospital administration of intravenous glucose-insulin-potassium in patients with suspected acute coronary syndromes: the IMMEDIATE randomized controlled trial. JAMA 9(307), 1925-1933 (2012). Catecholamine release in conjunction with an acute coronary syndrome induces metabolic changes that impair the situation for the ischemic myocardium. Attempts have been made to improve the prognosis in patients with acute coronary syndrome by means of infusing glucose-insulin-potassium in order to improve glucose metabolism and decrease beta-oxidation of free fatty acids. A trial, IMMEDIATE, tested this concept in a new way by initiating glucose-insulin-potassium during transportation to hospital, is discussed in this article.
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Mitochondrial haplogroups associated with lifestyle-related diseases and longevity in the Japanese population.
Nishigaki, Y, Fuku, N, Tanaka, M
Geriatrics & gerontology international. 2010;:S221-35
Abstract
Recently published results on the association between metabolic syndrome, type 2 diabetes, myocardial infarction or atherothrombotic cerebral infarction and Japanese major haplogroups based on the comprehensive analysis of mitochondrial genome polymorphisms (mtSNP) in the coding region of human mitochondrial DNA (mtDNA), and longevity-related haplogroups are described in the present review. Our aim was to provide information that would allow us to predict the genetic risk for lifestyle-related diseases and thereby contribute to the primary prevention of these conditions. The mitochondrial genome variation is so large that a given haplogroup might consist of various subhaplogroups carrying unique and presumably functional mtSNP. The frequency of each subhaplogroup is sometimes only a few percent. Therefore, large-scale association study is necessary for elucidating the impact of each subhaplogroup on the susceptibility to various common diseases.
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ALLHAT findings revisited in the context of subsequent analyses, other trials, and meta-analyses.
Wright, JT, Probstfield, JL, Cushman, WC, Pressel, SL, Cutler, JA, Davis, BR, Einhorn, PT, Rahman, M, Whelton, PK, Ford, CE, et al
Archives of internal medicine. 2009;(9):832-42
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The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is reevaluated considering information from new clinical trials, meta-analyses, and recent subgroup and explanatory analyses from ALLHAT, especially those regarding heart failure (HF) and the association of drug treatment with new-onset diabetes mellitus (DM) and its cardiovascular disease (CVD) consequences. Chlorthalidone was superior to (1) doxazosin mesylate in preventing combined CVD (CCVD) (risk ratio [RR], 1.20; 95% confidence interval [CI], 1.13-1.27), especially HF (RR, 1.80; 95% CI, 1.40-2.22) and stroke (RR, 1.26; 95% CI, 1.10-1.46); (2) lisinopril in preventing CCVD (RR, 1.10; 95% CI, 1.05-1.16), including stroke (in black persons only) and HF (RR, 1.20; 95% CI, 1.09-1.34); and (3) amlodipine besylate in preventing HF, overall (by 28%) and in hospitalized or fatal cases (by 26%). Central independent blinded reassessment of HF hospitalizations confirmed each comparison. Results were consistent by age, sex, race (except for stroke and CCVD), DM status, metabolic syndrome status, and renal function level. Neither amlodipine nor lisinopril was superior to chlorthalidone in preventing end-stage renal disease overall, by DM status, or by renal function level. In the chlorthalidone arm, new-onset DM was not significantly associated with CCVD (RR, 0.96; 95% CI, 0.88-2.42). Evidence from subsequent analyses of ALLHAT and other clinical outcome trials confirm that neither alpha-blockers, angiotensin-converting enzyme inhibitors, nor calcium channel blockers surpass thiazide-type diuretics (at appropriate dosage) as initial therapy for reduction of cardiovascular or renal risk. Thiazides are superior in preventing HF, and new-onset DM associated with thiazides does not increase CVD outcomes.