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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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Effect of atorvastatin on lipogenic, inflammatory and thrombogenic markers in women with the metabolic syndrome.
Velarde, GP, Choudhary, N, Bravo-Jaimes, K, Smotherman, C, Sherazi, S, Kraemer, DF
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2021;(2):634-640
Abstract
BACKGROUND AND AIM Specific drug therapy to target the underlying proinflammatory and prothrombotic state in patients with metabolic syndrome (MS) is lacking. We sought to study the effect of high-intensity atorvastatin on markers of lipogenesis, inflammation and thrombogenesis, in women with MS in the absence of cardiovascular disease or diabetes. METHODS AND RESULTS This randomized double-blinded controlled trial included 88 women with MS (according to National Cholesterol Education Panel Adult Treatment Panel III criteria) and low atherosclerotic cardiovascular risk. Participants were randomized to receive atorvastatin 80 mg or matching placebo. Thrombogenic, lipogenic and inflammatory markers were collected at the time of enrollment, after a 6-week dietary run-in phase (time of randomization), and at 6- and 12-weeks after randomization. At 6 weeks post-randomization, there was significant reduction in total cholesterol, low density lipoprotein cholesterol, triglycerides, apolipoprotein-B (Apo-B) and Apo-B/Apo-A1 ratio in the atorvastatin arm compared to placebo. This difference persisted at 12-weeks post randomization. There was no significant difference in fasting blood glucose, high-density lipoprotein cholesterol, high sensitivity C-reactive protein, serum leptin, Apo-A1, intercellular adhesion molecule 1 and platelet activity. A significant increase in vascular adhesion molecule 1 at 6 and 12 weeks was seen within the atorvastatin arm. No difference was observed in blood pressure and waist circumference. CONCLUSIONS In conclusion, high-intensity atorvastatin has an early and significant impact on lipoproteins and apolipoproteins but did not lower inflammatory, thrombogenic or biomarkers of platelet activity and aggregation in women with MS. The use of statins for primary prevention in these patients should be further explored.
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The challenge of multiple cardiovascular risk factor control outside Western Europe: Findings from the International ChoLesterol management Practice Study.
Blom, DJ, Santos, RD, Daclin, V, Mercier, F, Ruiz, AJ, Danchin, N, ,
European journal of preventive cardiology. 2020;(13):1403-1411
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BACKGROUND Comprehensive control of multiple cardiovascular risk factors reduces cardiovascular risk but is difficult to achieve. DESIGN A multinational, cross-sectional, observational study. METHODS The International ChoLesterol management Practice Study (ICLPS) investigated achievement of European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guideline low-density lipoprotein cholesterol (LDL-C) targets in patients receiving lipid-modifying therapy in countries outside Western Europe. We examined the rate of, and association between, control of multiple risk factors in ICLPS participants with dyslipidaemia, diabetes and hypertension (N = 2377). RESULTS Mean (standard deviation) age of patients was 61.4 (10.4) years; 51.3% were male. Type 2 diabetes was the most common form of diabetes (prevalence, 96.9%). The prevalence of metabolic syndrome was 67.8%, obesity 40.4%, atherosclerotic disease 39.6% and coronary artery disease 33.5%. All patients were at high (38.2%) or very high (61.8%) cardiovascular risk according to ESC/EAS guidelines. Body mass index (BMI) was <25 kg/m2 in 20.3% of patients, 62.8% had never smoked and 25.2% were former smokers. Overall, 12.2% achieved simultaneous control of LDL-C, diabetes and blood pressure. Risk factor control was similar across all participating countries. The proportion of patients achieving individual guideline-specified treatment targets was 43.9% for LDL-C, 55.5% for blood pressure and 39.3% for diabetes. Multiple correspondence analysis indicated that control of LDL-C, control of blood pressure, control of diabetes, BMI and smoking were associated. CONCLUSION Comprehensive control of multiple cardiovascular risk factors in high-risk patients is suboptimal worldwide. Failure to control one risk factor is associated with poor control of other risk factors.
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Pros and cons for use of statins in people with coronavirus disease-19 (COVID-19).
Subir, R, Jagat J, M, Kalyan K, G
Diabetes & metabolic syndrome. 2020;(5):1225-1229
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BACKGROUND AND AIMS Morbidity and mortality from coronavirus disease 2019 (COVID-19) is higher among people with diabetes mellitus (DM), hypertension, and cardiovascular disease (CVD). Statins are used in the majority of people with DM and CVD. This mini-review discusses the current understanding of benefit-risk ratio of use of statins in COVID-19. METHODS We searched PubMed database using specific keywords related to our aims till June 12, 2020. Full text of relevant articles published in English language were retrieved and reviewed. RESULTS Statins, with their immunomodulatory, anti-inflammatory, anti-thrombotic, and anti-oxidant properties, have the potential to reduce severity of lung injury in, and mortality from, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) infections. Statin-induced upregulation of angiotensin-converting enzyme-2 (ACE2) has the potential to reduce lung injury from excess angiotensin II. By disrupting lipid rafts, statins have the potential to reduce viral entry into cells. However, benefit-risk ratio of its complex interaction with MYD88 gene expression on outcomes in COVID-19, and the putative role of low serum LDL cholesterol in increasing severity of SARS-CoV2 infection need further clarification. CONCLUSIONS People with COVID-19, who are already on statins for an underlying co-morbid condition, should continue on it unless there are specific contraindications. De-novo use of statins in people with COVID-19 with no underlying co-morbidity might be beneficial but awaits substantiation in clinical trials; till that time, de novo use of statins in COVID 19 should be limited to a clinical trial setting.
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Effectiveness of interventions for the reversal of a metabolic syndrome diagnosis: An update of a meta-analysis of mixed treatment comparison studies.
Guzmán, A, Navarro, E, Obando, L, Pacheco, J, Quirós, K, Vásquez, L, Castro, M, Ramírez, F
Biomedica : revista del Instituto Nacional de Salud. 2019;(4):647-662
Abstract
Introduction: Identifying the most effective interventions to reverse the metabolic syndrome can be key in the design of clinical strategies to prevent progression to type 2 diabetes mellitus and cardiovascular disease. Objective: To estimate the effect size of the interventions used for the reversal of metabolic syndrome. Materials and methods: We searched in Embase and Medline databases for randomized clinical trials with an outcome defined as the reversal of the metabolic syndrome diagnosis. We classified the interventions in four dimensions: 1) lifestyle (diet and exercise); 2) pharmaceuticals; 3) a combination of both, and 4) control groups, and we conducted a mixed treatment comparison analysis. Results: Additional to the previous meta-analysis published by Dunkley, et al. in 2012, we dentified two other studies. Lifestyle interventions had 2.61 more chances to achieve the reversal of the metabolic syndrome than the control group, with a credible interval between 1.00 and 5.47. Pharmaceutical treatments showed a 3.39 higher chance of reversing the syndrome compared with the control group, but the credible interval was estimated from 0.81 to 9.99. Lifestyle interventions had 1.59 more chance of reversal than the pharmaceutical treatments. Conclusion: Diet and physical activity-based interventions had a higher probability of effectiveness to reverse a metabolic syndrome diagnosis.
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Genetic Variants Associated With Plasma Lipids Are Associated With the Lipid Response to Niacin.
Tuteja, S, Qu, L, Vujkovic, M, Dunbar, RL, Chen, J, DerOhannessian, S, Rader, DJ
Journal of the American Heart Association. 2018;(19):e03488
Abstract
Background Niacin is a broad-spectrum lipid-modulating drug, but its mechanism of action is unclear. Genome-wide association studies have identified multiple loci associated with blood lipid levels and lipoprotein (a). It is unknown whether these loci modulate response to niacin. Methods and Results Using data from the AIM - HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL /High Triglycerides and Impact on Global Health Outcomes) trial (n=2054 genotyped participants), we determined whether genetic variations at validated loci were associated with a differential change in plasma lipids and lipoprotein (a) 1 year after randomization to either statin+placebo or statin+niacin in a variant-treatment interaction model. Nominally significant interactions ( P<0.05) were found for genetic variants in MVK , LIPC , PABPC 4, AMPD 3 with change in high-density lipoprotein cholesterol; SPTLC 3 with change in low-density lipoprotein cholesterol; TOM 1 with change in total cholesterol; PDXDC 1 and CYP 26A1 with change in triglycerides; and none for lipoprotein (a). We also investigated whether these loci were associated with cardiovascular events. The risk of coronary disease related death was higher in the minor allele carriers at the LIPC locus in the placebo group (odds ratio 2.08, 95% confidence interval 1.11-3.90, P=0.02) but not observed in the niacin group (odds ratio 0.89, 95% confidence interval 0.48-1.65, P=0.7); P-interaction =0.02. There was a greater risk for acute coronary syndrome (odds ratio 1.85, 95% confidence interval 1.16-2.77, P=0.02) and revascularization events (odds ratio 1.64, 95% confidence interval 1.2-2.22, P=0.002) in major allele carriers at the CYP 26A1 locus in the placebo group not seen in the niacin group. Conclusions Genetic variation at loci previously associated with steady-state lipid levels displays evidence for lipid response to niacin treatment. Clinical Trials Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT00120289.
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Dyslipidaemia in nephrotic syndrome: mechanisms and treatment.
Agrawal, S, Zaritsky, JJ, Fornoni, A, Smoyer, WE
Nature reviews. Nephrology. 2018;(1):57-70
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Nephrotic syndrome is a highly prevalent disease that is associated with high morbidity despite notable advances in its treatment. Many of the complications of nephrotic syndrome, including the increased risk of atherosclerosis and thromboembolism, can be linked to dysregulated lipid metabolism and dyslipidaemia. These abnormalities include elevated plasma levels of cholesterol, triglycerides and the apolipoprotein B-containing lipoproteins VLDL and IDL; decreased lipoprotein lipase activity in the endothelium, muscle and adipose tissues; decreased hepatic lipase activity; and increased levels of the enzyme PCSK9. In addition, there is an increase in the plasma levels of immature HDL particles and reduced cholesterol efflux. Studies from the past few years have markedly improved our understanding of the molecular pathogenesis of nephrotic syndrome-associated dyslipidaemia, and also heightened our awareness of the associated exacerbated risks of cardiovascular complications, progressive kidney disease and thromboembolism. Despite the absence of clear guidelines regarding treatment, various strategies are being increasingly utilized, including statins, bile acid sequestrants, fibrates, nicotinic acid and ezetimibe, as well as lipid apheresis, which seem to also induce partial or complete clinical remission of nephrotic syndrome in a substantial percentage of patients. Future potential treatments will likely also include inhibition of PCSK9 using recently-developed anti-PCSK9 monoclonal antibodies and small inhibitory RNAs, as well as targeting newly identified molecular regulators of lipid metabolism that are dysregulated in nephrotic syndrome.
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Effectiveness of Lipid-Lowering Statin Therapy in Patients With and Without Psoriasis.
Ports, WC, Fayyad, R, DeMicco, DA, Laskey, R, Wolk, R
Clinical drug investigation. 2017;(8):775-785
Abstract
BACKGROUND Psoriasis is associated with dyslipidemia and metabolic syndrome, and has been linked to an increased cardiovascular risk. The aim of this study was to compare baseline characteristics and effects of statin therapy on lipid levels and cardiovascular outcomes in patients with and without psoriasis. METHODS This post-hoc analysis assessed patients from one primary cardiovascular prevention statin trial (Collaborative AtoRvastatin Diabetes Study [CARDS]) and two secondary cardiovascular prevention statin trials (Treating to New Targets [TNT] and Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL]). Baseline characteristics, lipid changes from baseline, and cardiovascular event rates were analyzed. TNT and IDEAL data were pooled. RESULTS Baseline characteristics and lipid profiles differed minimally in patients with and without psoriasis. In CARDS and TNT/IDEAL, similar apolipoprotein B, total cholesterol, and low-density lipoprotein cholesterol reductions occurred with statin therapy in patients with or without psoriasis. High-dose atorvastatin significantly reduced cardiovascular events vs. standard/low-dose statins in patients without psoriasis in TNT/IDEAL; similar numeric differences in event rates were observed in patients with psoriasis. CONCLUSIONS In this post-hoc analysis, statins improved lipid levels and cardiovascular outcomes in patients with and without psoriasis, supporting statin use in patients with psoriasis. Trial registration (ClinicalTrials.gov) NCT00327418, registered 16 May, 2006; NCT00327691, registered 16 May, 2006; NCT00159835, registered 8 September, 2005.
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NASH Therapy: omega 3 supplementation, vitamin E, insulin sensitizers and statin drugs.
Caldwell, S
Clinical and molecular hepatology. 2017;(2):103-108
Abstract
Non-alcoholic steatohepatitis (NASH) is the more aggressive form of non-alcoholic fatty liver disease (NAFLD). NASH can progress to hepatic fibrosis, cirrhosis, portal hypertension and primary liver cancer. Therapy is evolving with a substantial number of trials of promising new agents now in progress. In this article however, we will examine data for several older forms of therapy which have been fairly extensively studied over the years: Polyunsaturated Fatty Acid (PUFA) supplements, vitamin E, insulin sensitizing agents with a focus on pioglitazone and statin agents. Early interest in PUFA derived from their potential benefit in cardio-metabolic disease and the close association of NAFLD/NASH with Metabolic Syndrome. Results have been variable although most studies show reduction of liver fat without other major effects and their effects are influenced by concomitant weight loss and underlying genetic factors. Vitamin E has had some efficacy in pediatric NASH but questionable efficacy in even mild NASH among adults. Pioglitazone has shown significant histological benefit in a number of trials but concern over side-effects (especially weight gain) have dampened enthusiasm. A newer insulin sensitizer, liraglutide, has also shown promise in a small randomized, controlled trial. Very limited data exists regarding the histological effects of the statins in NASH and these agents appear to be fairly neutral with neither clear cut benefit nor detriment. Their use is best guided by cardiovascular risks rather than liver histology.
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How to assess and manage cardiovascular risk associated with lipid alterations beyond LDL.
Averna, M, Stroes, E, ,
Atherosclerosis. Supplements. 2017;:16-24
Abstract
BACKGROUND AND AIMS The maintenance of clinically recommended levels of low-density lipoprotein cholesterol (LDL-C) through a statin therapy is a gold standard in the management of patients with dyslipidaemia and cardiovascular disease (CVD). However, even when LDL-C levels are at or below clinically recommended target levels, residual cardiovascular (CV) risk still remains. Therefore, assessing lipoproteins beyond LDL-C in managing CV risk is imperative. METHODS A working group of clinical experts have assessed the role of lipoproteins other than LDL-C in identifying the CV risk in patients with dyslipidaemia and CVD and in the management of atherogenic dyslipidaemia associated with a number of other diseases. The recommendations, in line with the European guidelines, are presented. RESULTS A thorough evaluation of clinical data by the expert working group resulted in recommendations to consider non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apoB), remnant cholesterol and lipoprotein(a) (Lp[a]) as biomarkers of residual CV risk in patients with CVD. Elevated Lp(a) levels were also suggested to be a causal factor. The experts highlighted the significance of non-HDL-C and triglycerides (TG) in atherogenic dyslipidaemia associated with type 2 diabetes, metabolic syndrome, chronic kidney disease (CKD) and familial combined hyperlipidaemia (FCH). The working group recommended combinatorial therapeutic approaches in high-risk patients, including agents impacting on TG and HDL-C levels. CONCLUSIONS Evaluation of a lipoprotein landscape when LDL-C levels remain low strongly supports the role of non-HDL-C, Lp(a) and TGs in identifying patients with increased residual risk of CV and in selecting their treatment strategy.