Maria-Corina Serban

Lipid-modifying effects of nutraceuticals: An evidence-based approach

The present review provides an up-to-date summary of the findings on the lipid-lowering effects of the most important nutraceuticals and functional foods. Based on current knowledge, nutraceuticals might exert significant lipid-lowering, and their use has several advantages: A number of important questions remain to be addressed, including whether longer durations of therapy would result in a better response and the exact safety profile of nutraceuticals, especially at doses higher than those consumed in an average diet. Additionally, data regarding the effects of nutraceutical supplementation on the incidence of cardiovascular outcomes are lacking, and it is not clear whether additional lipid lowering by nutraceuticals can modify the residual cardiovascular risk that remains after statin therapy.

Lipid lowering nutraceuticals in clinical practice: position paper from an International Lipid Expert Panel

Arrigo F.G. Cicero, University of Bologna Alessandro Colletti, University of Bologna Gani Bajraktari, University Clinical Centre of Kosovo Olivier Descamps, Centres Hospitaliers Jolimont Dragan M. Djuric, University of Belgrade Marat Ezhov, Russian Cardiology Research and Production Centre Zlatko Fras, University Medical Centre Ljubljana Niki Katsiki, Aristotle University of Thessaloniki Michel Langlois, AZ Sint-Jan Hospital Gustavs Latkovskis, University of Latvia

Proprotein Convertase Subtilisin/Kexin 9 Inhibitors: An Emerging Lipid-Lowering Therapy?

Proprotein convertase subtilisin/kexin 9 (PCSK9) is part of the proteinase K subfamily of subtilases and plays a key role in lipid metabolism. It increases degradation of the low-density lipoprotein receptor (LDL-R), modulates cholesterol metabolism and transport, and contributes to the production of apolipoprotein B (apoB) in intestinal cells. Exogenous PCSK9 modifies the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and acyl coenzyme A:cholesterol acyltransferase and enhances secretion of chylomicrons by modulating production of lipids and apoB-48. Statins increase PCSK9 messenger RNA expression and attenuate the capacity to increase LDL-R levels. Therefore, the inhibition of PCSK9 in combination with statins provides a promising approach for lowering low-density lipoprotein cholesterol (LDL-C) concentrations. This review will address new therapeutic strategies targeting PCSK9, including monoclonal antibodies, antisense oligonucleotides, small interfering RNAs, and other small molecule inhibitors. Further studies are still needed to determine the efficacy and safety of the PCSK9 inhibitors not only to decrease LDL-C but also to investigate the potential underlying mechanisms involved and to test whether these compounds actually reduce cardiovascular end points and mortality.

Clinical implications of the IMPROVE-IT trial in the light of current and future lipid-lowering treatment options.

ABSTRACT Introduction: A residual risk of morbidity and mortality from cardiovascular (CV) disease remains despite statin therapy. This situation has generated an interest in finding novel approaches of combining statins with other lipid-lowering agents, or finding new lipid and non-lipid targets, such as triglycerides, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, cholesterol ester transfer protein (CETP), lipoprotein (a), fibrinogen or C-reactive protein. Areas covered: The recent results from the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) demonstrated an incremental clinical benefit when ezetimibe, a non-statin agent, was added to simvastatin therapy. Expert opinion: The results from IMPROVE-IT revalidated the concept that low-density lipoprotein cholesterol (LDL-C) levels are a clinically relevant treatment goal. This trial also suggested that further decrease of LDL-C levels (53 vs. 70 mg/dl; 1.4 vs. 1.8 mmol/l) was more beneficial in lowering CV events. This “even lower is even better” evidence for LDL-C levels may influence future guidelines and the use of new drugs. Furthermore, these findings make ezetimibe a more realistic option to treat patients with statin intolerance or those who cannot achieve LDL-C targets with statin monotherapy.

Lipid profile and glucose changes after supplementation with astaxanthin: a systematic review and meta-analysis of randomized controlled trials.

Introduction Many studies have shown that oral supplementation with astaxanthin may be a novel potential treatment for inflammation and oxidative stress in cardiovascular diseases, but evidence of the effects on lipid profile and glucose is still inconclusive. Therefore, we performed a meta-analysis to evaluate the efficacy of astaxanthin supplementation on plasma lipid and glucose concentrations. Material and methods The search included PubMed, Cochrane Library, Scopus, and EMBASE (up to November 27, 2014) to identify randomized controlled trials (RCTs) investigating the effects of astaxanthin supplementation on lipid profile and glucose levels. Two independent reviewers extracted data on study characteristics, methods and outcomes. Results Seven studies meeting inclusion criteria with 280 participants were selected for this meta-analysis; 163 participants were allocated to the astaxanthin supplementation group and 117 to the control group. A random-effect meta-analysis of data from 7 RCTs (10 treatment arms) did not show any significant effect of supplementation with astaxanthin on plasma concentrations of total cholesterol (weighted mean difference (WMD): –1.52 mg/dl, 95% CI: –8.69 to –5.66, p = 0.679), LDL-C (WMD: +1.25 mg/dl, 95% CI: –6.70 to +9.21, p = 0.758), HDL-C (WMD: +1.75 mg/dl, 95% CI: –0.92 to +4.42, p = 0.199), triglycerides (WMD: –4.76 mg/dl, 95% CI: –21.52 to +12.00, p = 0.578), or glucose (WMD: –2.65 mg/dl, 95% CI: –5.84 to +0.54, p = 0.103). All these effect sizes were robust, and omission of any of the included studies did not significantly change the overall estimate. Conclusions This meta-analysis of data from 10 RCT arms did not indicate a significant effect of supplementation with astaxanthin on plasma lipid profile, but a slight glucose-lowering effect was observed. Further, well-designed trials are necessary to validate these results.

Discussion around statin discontinuation in older adults and patients with wasting diseases

Statins are usually selected as the first-line therapy to lower plasma levels of low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD) morbidity and mortality. They reduce the risk of myocardial infarction, stroke and CVD mortality by about 25–30%. That is one of the reasons why all current clinical guidelines ‘virtually mandate’ lifetime use of statins once they are started, thus becoming a challenge for the patients due to their possible side effects. Furthermore, there has been recently a tendency towards maximizing the strength of statin treatment, sometimes with greater doses or potent forms. The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial showed that the combination with ezetimibe/simvastatin 10mg/40mg let to an absolute 2.0% reduction (relative risk reduction: 6.4%) of the risk of CV events in contrast to simvastatin 40mg alone. The trial also demonstrated that the patients with obtained very low LDL-C levels <30mg/dL experienced no discrepancies in adverse effects than those with higher LDL-C levels. ODYSSEY LONG-TERM and the Open-Label Study of Long-term Evaluation against LDL-C trials with proprotein convertase subtilisin/kexin type 9 inhibitors also supported the hypothesis ‘the lower the better’ for LDL-C levels, generating more arguments for lower LDL-C targets <50mg/dL (1.3mmol/L), in contrast with the current targets <70mg/dL (1.8mmol/L) for patients at the highest risk. These results are in line with the 2013 American College of Cardiology/American Heart Association guidelines, which advise the use of high-intensity statin therapy and extend its use to more categories susceptible to CVD. Taking into account still poor to moderate statin therapy control in the high-risk and highest-risk patients (even 50% of patients are non-adherent to therapy after 2 years), as well as the aforementioned data, more intense targets seem to be very important; however, on the other hand, high-intensity statin therapy might also increase the risk of statin-related side effects and statin discontinuation rate due to this fact.

Adherence to High-Intensity Statins Following a Myocardial Infarction Hospitalization Among Medicare Beneficiaries

Importance High-intensity statins are recommended following myocardial infarction. However, patients may not continue taking this medication with high adherence. Objective To estimate the proportion of patients filling high-intensity statin prescriptions following myocardial infarction who continue taking this medication with high adherence and to analyze factors associated with continuing a high-intensity statin with high adherence after myocardial infarction. Design, Setting, and Participants Retrospective cohort study of Medicare patients following hospitalization for myocardial infarction. Medicare beneficiaries aged 66 to 75 years (n = 29 932) and older than 75 years (n = 27 956) hospitalized for myocardial infarction between 2007 and 2012 who filled a high-intensity statin prescription (atorvastatin, 40-80 mg, and rosuvastatin, 20-40 mg) within 30 days of discharge. Beneficiaries had Medicare fee-for-service coverage including pharmacy benefits. Exposures Sociodemographic, dual Medicare/Medicaid coverage, comorbidities, not filling high-intensity statin prescriptions before their myocardial infarction (ie, new users), and cardiac rehabilitation and outpatient cardiologist visits after discharge. Main Outcomes and Measures High adherence to high-intensity statins at 6 months and 2 years after discharge was defined by a proportion of days covered of at least 80%, down-titration was defined by switching to a low/moderate-intensity statin with a proportion of days covered of at least 80%, and low adherence was defined by a proportion of days covered less than 80% for any statin intensity without discontinuation. Discontinuation was defined by not having a statin available to take in the last 60 days of each follow-up period. Results Approximately half of the beneficiaries were women and fourth-fifths were white. At 6 months and 2 years after discharge among beneficiaries 66 to 75 years of age, 17 633 (58.9%) and 10 308 (41.6%) were taking high-intensity statins with high adherence, 2605 (8.7%) and 3315 (13.4%) down-titrated, 5182 (17.3%) and 4727 (19.1%) had low adherence, and 3705 (12.4%) and 4648 (18.8%) discontinued their statin, respectively. The proportion taking high-intensity statins with high adherence increased between 2007 and 2012. African American patients, Hispanic patients, and new high-intensity statin users were less likely to take high-intensity statins with high adherence, and those with dual Medicare/Medicaid coverage and more cardiologist visits after discharge and who participated in cardiac rehabilitation were more likely to take high-intensity statins with high adherence. Results were similar among beneficiaries older than 75 years of age. Conclusions and Relevance Many patients filling high-intensity statins following a myocardial infarction do not continue taking this medication with high adherence for 2 years postdischarge. Interventions are needed to increase high-intensity statin use and adherence after myocardial infarction.

Evidence-based assessment of lipoprotein(a) as a risk biomarker for cardiovascular diseases – some answers and still many questions

Abstract The present article is aimed at outlining the current state of knowledge regarding the clinical value of lipoprotein(a) (Lp(a)) as a marker of cardiovascular disease (CVD) risk by summarizing the results of recent clinical studies, meta-analyses and systematic reviews. The literature supports the predictive value of Lp(a) on CVD outcomes, although the effect size is modest. Lp(a) would also appear to have an effect on cerebrovascular outcomes, however the effect appears even smaller than that for CVD outcomes. Consideration of apolipoprotein(a) (apo(a)) isoforms and LPA genetics in relation to the simple assessment of Lp(a) concentration may enhance clinical practice in vascular medicine. We also describe recent advances in Lp(a) research (including therapies) and highlight areas where further research is needed such as the measurement of Lp(a) and its involvement in additional pathophysiological processes.

Lipid-modifying effects of krill oil in humans: systematic review and meta-analysis of randomized controlled trials

Context Some experimental and clinical trials have shown that krill oil, extracted from small red crustaceans, might be an effective lipid-modifying agent, but the evidence is not conclusive. Objective The effect of krill oil supplements on plasma lipid concentrations was assessed through a systematic review of the literature and a meta-analysis of available randomized controlled trials. Data sources PubMed and Scopus were searched up to March 25, 2016, to identify RCTs investigating the effect of krill oil supplements on plasma lipids. Study selection Randomized controlled trials that investigated the impact of at least 2 weeks of supplementation with krill oil on plasma/serum concentrations of at least one of the main lipid parameters (ie, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglycerides) and that reported sufficient information on plasma/serum lipid levels at baseline and at the end of study in both krill oil and control groups were eligible for inclusion. Data extraction Two reviewers independently extracted the following data: first authors name, year of publication, study location, study design, number of participants in the krill oil and control groups, dosage of krill oil, type of control allocation, treatment duration, demographic characteristics of study participants, and baseline and follow-up plasma concentrations of lipids. Effect size was expressed as the weighted mean difference (WMD) and 95% confidence interval (95%CI). Results Meta-analysis of data from 7 eligible trials (14 treatment arms) with 662 participants showed a significant reduction in plasma concentrations of low-density lipoprotein cholesterol (WMD, -15.52 mg/dL; 95%CI, -28.43 to -2.61; P = 0.018) and triglycerides (WMD, -14.03 mg/dL; 95%CI, -21.38 to -6.67; P < 0.001) following supplementation with krill oil. A significant elevation in plasma concentrations of high-density lipoprotein cholesterol was also observed (WMD, 6.65 mg/dL; 95%CI, 2.30 to 10.99; P = 0.003), while a reduction in plasma concentrations of total cholesterol did not reach statistical significance (WMD, -7.50 mg/dL; 95%CI, -17.94 to 2.93; P = 0.159). Conclusion Krill oil supplementation can reduce low-density lipoprotein cholesterol and triglycerides. Additional clinical studies with more participants are needed to assess the impact of krill oil supplementation on other indices of cardiometabolic risk and on the risk of cardiovascular outcomes.

The effect of statins on cardiovascular outcomes by smoking status: A systematic review and meta-analysis of randomized controlled trials

&NA; Smoking is an important risk factor for cardiovascular disease (CVD) morbidity and mortality. The impact of statin therapy on CVD risk by smoking status has not been fully investigated. Therefore we assessed the impact of statin therapy on CVD outcomes by smoking status through a systematic review of the literature and meta‐analysis of available randomized controlled trials (RCTs). The literature search included EMBASE, ProQuest, CINAHL and PUBMED databases to 30 January 2016 to identify RCTs that investigated the effect of statin therapy on cumulative incidence of major CVD endpoints (e.g. non‐fatal myocardial infarction, revascularization, unstable angina, and stroke). Relative risks (RR) ratios were calculated from the number of events in different treatment groups for both smokers and non‐smokers. Finally 11 trials with 89,604 individuals were included. The number of smokers and non‐smokers in the statin groups of the analyzed studies was 8826 and 36,090, respectively. The RR for major CV events was 0.73 (95% confidence interval [CI]: 0.67–0.81; p < 0.001) in nonsmokers and 0.72 (95%CI: 0.64–0.81; p < 0.001) in smokers. Moderate to high heterogeneity was observed both in non‐smokers (I2 = 77.1%, p < 0.001) and in smokers (I2 = 51.6%, p = 0.024) groups. Smokers seemed to benefit slightly more from statins than non‐smokers according to the number needed to treat (NNT) analysis (23.5 vs 26.8) based on RRs applied to the control event rates. The number of avoided events per 1000 individuals was 42.5 (95%CI: 28.9–54.6) in smokers and 37.3 (95%CI: 27.2–46.4) in non‐smokers. In conclusion, this meta‐analysis suggests that the effect of statins on CVD is similar for smokers and non‐smokers, but in terms of NNTs and number of avoided events, smokers seem to benefit more although non‐significantly.