The role of bempedoic acid in the management of dyslipidaemia

Bempedoic acid is a new oral lipid-lowering therapy which has been licenced for use in the United Kingdom. It can be used alone, with a statin, or with other lipid-lowering therapies where the target level for low density lipoprotein has not been achieved with these therapies alone. Bempedoic acid with ezetimibe can be prescribed for people who are unable to tolerate statins. This combination has received NICE approval following a technology appraisal. This paper discusses the place for of bempedoic acid as a lipid lowering drug and consider the mode of action, licensed indications, adverse drug reactions and the NICE technology appraisal recommendations.

Use of electronic patient data overview with alerts in primary care increases prescribing of lipid-lowering medications in patients with type 2 diabetes

Aims/hypothesis We aimed to assess whether general practices (GPs) using an electronic disease management program (DMP) with population overviews, including alerts when patients failed to receive guideline-recommended prescription medications, increased prescriptions of lipid-lowering drugs for patients with type 2 diabetes with no history of lipid-lowering treatment. Methods This observational study included 165 GPs that reached a high level of use of the DMP in 2012 and a control group of 135 GPs who reached a high level of use in 2013 and, hence, who were less exposed to the DMP throughout 2012. A binary measure for having been prescribed and filled lipid-lowering drugs at any time within a 12-month exposure period was derived for all patients with type 2 diabetes who did not receive a prescription for lipid-lowering drugs in the baseline year prior to the study period (i.e. 2011). Results were derived using ORs from multivariate logistic regression analyses. Subgroup stratification based on age, sex, diabetes duration, deprivation status and Charlson Comorbidity Index (CCI) score was conducted and assessed. Placebo tests were carried out to assess bias from selection to treatment. Results Patients who did not receive a prescription of lipid-lowering drugs in the year prior to being listed with GPs that used the DMP had statistically significant greater odds of receiving a prescription of lipid-lowering medications when compared with individuals who attended control GPs (OR 1.23 [95% CI 1.09, 1.38]). When the analysis period was shifted back by 2 years, no significant differences in lipid-lowering drug prescription between the two groups were found to occur, which indicates that these results were not driven by selection bias. Subgroup analyses showed that the increase in lipid-lowering drug prescriptions was primarily driven by changes among male participants (OR 1.32 [95% CI 1.12, 1.54]), patients aged 60–70 years (OR 1.40 [95% CI 1.13, 1.74]), patients with a diabetes duration of ≤5 years (OR 1.33 [95% CI 1.13, 1.56]), non-deprived patients (OR 1.25 [95% CI 1.08, 1.45]) and patients without comorbidities (CCI score = 0; OR 1.27 [95% CI 1.11, 1.45]). Conclusions/interpretation Access to population overviews using a DMP with alerts of clinical performance measures with regard to adhering to guideline-recommended prescription of medications can increase GP prescriptions of lipid-lowering drugs. Graphical abstract

Direct activation of endothelial cells by SARS-CoV-2 nucleocapsid protein is blocked by Simvastatin

Emerging evidence suggests that endothelial activation plays a central role in the pathogenesis of acute respiratory distress syndrome (ARDS) and multi-organ failure in patients with COVID-19. However, the molecular mechanisms underlying endothelial activation in COVID-19 patients remain unclear. In this study, the SARS-CoV-2 viral proteins that potently activate human endothelial cells were screened to elucidate the molecular mechanisms involved in endothelial activation. It was found that nucleocapsid protein (NP) of SARS-CoV-2 significantly activated human endothelial cells through TLR2/NF-κB and MAPK signaling pathways. Moreover, by screening a natural microbial compound library containing 154 natural compounds, simvastatin was identified as a potent inhibitor of NP-induced endothelial activation. Remarkablely, though the protein sequences of N proteins from coronaviruses are highly conserved, only NP from SARS-CoV-2 induced endothelial activation. The NPs from other coronaviruses such as SARS-CoV, MERS-CoV, HUB1-CoV and influenza virus H1N1 did not activate endothelial cells. These findings are well consistent with the results from clinical investigations showing broad endotheliitis and organ injury in severe COVID-19 patients. In conclusion, the study provides insights on SARS-CoV-2-induced vasculopathy and coagulopathy, and suggests that simvastatin, an FDA-approved lipid-lowering drug, may benefit to prevent the pathogenesis and improve the outcome of COVID-19 patients. IMPORTANCE Coronavirus disease 2019 (COVID-19), caused by the betacoronavirus SARS-CoV-2, is a worldwide challenge for health-care systems. The leading cause of mortality in patients with COVID-19 is hypoxic respiratory failure from acute respiratory distress syndrome (ARDS). To date, pulmonary endothelial cells (ECs) have been largely overlooked as a therapeutic target in COVID-19, yet emerging evidence suggests that these cells contribute to the initiation and propagation of ARDS by altering vessel barrier integrity, promoting a pro-coagulative state, inducing vascular inflammation and mediating inflammatory cell infiltration. Therefore, a better mechanistic understanding of the vasculature is of utmost importance. In this study, we screened the SARS-CoV-2 viral proteins that potently activate human endothelial cells and found that nucleocapsid protein (NP) significantly activated human endothelial cells through TLR2/NF-κB and MAPK signaling pathways. Moreover, by screening a natural microbial compound library containing 154 natural compounds, simvastatin was identified as a potent inhibitor of NP-induced endothelial activation. Our results provide insights on SARS-CoV-2-induced vasculopathy and coagulopathy, and suggests that simvastatin, an FDA-approved lipid-lowering drug, may benefit to prevent the pathogenesis and improve the outcome of COVID-19 patients.

Umbrella Review on Non-Statin Lipid-Lowering Therapy

Dyslipidemia, particularly increased low-density lipoprotein cholesterol (LDL-C) levels, are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) events. There is an unmet need for ASCVD risk reduction even with the optimal use of statin therapy, which has led to an ongoing search for novel targets for cholesterol reduction to decrease ASCVD events. Objectives: The main aim of this review was to summarize current evidence on approved and emerging non-statin lipid-lowering therapies. Methods and Materials: Recent literature on U.S. FDA approved non-statin lipid-lowering therapies and evolving lipid-lowering drugs currently under development was reviewed. Results and Discussion: In the past 20 years, the emergence of non-statin cholesterol-lowering drugs has changed the landscape of dyslipidemia management. Food and Drug Administration approval of non-statin lipid-lowering therapies such as ezetimibe, proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors (evolocumab, alirocumab), bempedoic acid and combination of bempedoic acid and ezetimibe, evinacumab and other triglyceride-lowering agents (eg, icosapent ethyl) has emerged. The European Commission has also recently approved inclisiran for treatment of hypercholesterolemia and mixed hypercholesterolemia even though FDA has put the approval of this drug on hold. Recent guidelines have incorporated PCSK9 inhibitors to treat patients with primary hyperlipidemia and patients with very high-risk ASCVD, who could not achieve adequate lipid-lowering with combination therapy of maximally tolerated statin and ezetimibe. Icosapent ethyl use as an adjunct therapy to statins is also recommended to reduce the risk of ASCVD in patients with hypertriglyceridemia. Conclusion: Despite cost limitations, the uptake of PCSK9 inhibitors is increasing. Approval of bempedoic acid alone or in combination with ezetimibe has provided additional oral lipid-lowering drug alternatives to ezetimibe. Various lipid-lowering drug targets are under investigation.

Identifying Clusters of Adherence to Cardiovascular Risk Reduction Behaviors and Persistence with Medication in New Lipid-Lowering Drug Users. Impact on Healthcare Utilization

We sought to identify specific profiles of new lipid-lowering drug users based on adherence to a healthy lifestyle and persistence with medication, and to characterize co-morbidities, co-treatments, and healthcare utilization for each of the profiles identified. Observational study in 517 participants in the Aragon Workers’ Health Study (AWHS) without previous cardiovascular disease (CVD) and who initiated lipid-lowering therapy. Data were collected from workplace medical examinations and administrative health databases (2010–2018). Using cluster analysis, we identified distinct patient profiles based on persistence with therapy and lifestyle. We then compared characteristics, morbidity, and healthcare utilization across clusters. Participants were aggregated into four clusters based on persistence with therapy, smoking status, adherence to Mediterranean diet, and physical activity. In cluster 1 (n = 113), comprising those with a healthiest lifestyle (14.2% smokers, 84.0% with medium-high adherence to Mediterranean diet, high physical activity), 16.8% were persistent. In cluster 3 (n = 108), comprising patients with the least healthy lifestyle (100% smokers, poor adherence to the Mediterranean diet, low level of physical activity), all were non-persistent. Clusters 2 (n = 150) and 4 (n = 146) both comprised patients with intermediate lifestyle behaviors, but differed in terms of persistence (100 and 0%, respectively). Compared with other clusters, the burden of morbidity, cardiovascular score, and healthcare utilization were lower in cluster 1. The healthy adherer effect was only observed in new lipid-lowering drug users of certain profiles. Furthermore, we found that differences in adherence to lifestyle and medication recommendations for CVD prevention influenced morbidity burden and healthcare utilization.