Pharmacodynamic effect of bempedoic acid and statin combinations: predictions from a dose–response model

Aims Many patients are unable to achieve guideline-recommended LDL cholesterol (LDL-C) targets, despite taking maximally tolerated lipid-lowering therapy. Bempedoic acid, a competitive inhibitor of ATP citrate lyase, significantly lowers LDL-C with or without background statin therapy in diverse populations. Because pharmacodynamic interaction between statins and bempedoic acid is complex, a dose–response model was developed to predict LDL-C pharmacodynamics following administration of statins combined with bempedoic acid. Methods and results Bempedoic acid and statin dosing and LDL-C data were pooled from 14 phase 1–3 clinical studies. Dose–response models were developed for bempedoic acid monotherapy and bempedoic acid–statin combinations using previously published statin parameters. Simulations were performed using these models to predict change in LDL-C levels following treatment with bempedoic acid combined with clinically relevant doses of atorvastatin, rosuvastatin, simvastatin, and pravastatin. Dose–response models predicted that combining bempedoic acid with the lowest statin dose of commonly used statins would achieve a similar degree of LDL-C lowering as quadrupling that statin dose; for example, the predicted LDL-C lowering was 54% with atorvastatin 80 mg compared with 54% with atorvastatin 20 mg + bempedoic acid 180 mg, and 42% with simvastatin 40 mg compared with 46% with simvastatin 10 mg + bempedoic acid 180 mg. Conclusion These findings suggest bempedoic acid combined with lower statin doses offers similar LDL-C lowering compared with statin monotherapy at higher doses, potentially sparing patients requiring additional lipid-lowering therapies from the adverse events associated with higher statin doses.

The Role of Lipid and the Benefit of Statin in Augmenting Rifampicin Effectivity for a Better Leprosy Treatment

Although leprosy remains as a serious disease of the skin and nervous system, the current treatment is still lacking in its effectiveness. This literature review will explore the association of lipid and leprosy, as well as the potential of statin and other lipid-lowering agents as adjunctive drugs to combat leprosy. Articles were searched through the PubMed, EBSCOhost, and Google Scholar with the keywords: immunomodulation, lipid-body, lipids, leprosy, Mycobacterium leprae, pathogenesis, rifampin or rifampicin, and statins. A manual searching is also carried out to find an additional relevant information to make this literature review more comprehensive. The literatures showed that lipids are highly correlated with leprosy through alterations in serum lipid profile, metabolism, pathogenesis, and producing oxidative stress. Statins can diminish lipid utilization in the pathogenesis of leprosy and show a mycobactericidal effect by increasing the effectiveness of rifampicin and recover the function of macrophages. In addition, Statins have anti-inflammatory properties which may aid in preventing type I and II reactions in leprosy. Standard multidrug therapy might reduce the efficacy of statins, but the effect is not clinically significant. The statin dose-response curve also allows therapeutic response to be achieved with minimal dose. The various pleiotropic effects of statins make it a potential adjunct to standard treatment for leprosy in the future.

Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors Reduce Platelet Activation Modulating ox-LDL Pathways

Background: Proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) lower LDL-cholesterol and slow atherosclerosis preventing cardiovascular events. While it is known that circulating PCSK9 enhances platelet activation (PA) and that PCSK9i reduce it, the underlying mechanism is not still clarified. Methods: In a multicenter before–after study in 80 heterozygous familial hypercholesterolemia (HeFH) patients on treatment with maximum tolerated statin dose ± ezetimibe, PA, soluble-NOX2-derived peptide (sNOX2-dp), and oxidized-LDL (ox-LDL) were measured before and after six months of PCSK9i treatment. In vitro study investigates the effects of plasma from HeFH patients before and after PCK9i on PA in washed platelets (wPLTs) from healthy subjects. Results: Compared to baseline, PCSK9i reduced the serum levels of LDL-c, ox-LDL, Thromboxane (Tx) B2, sNOX2-dp, and PCSK9 (p < 0.001). The decrease of TxB2 correlates with that of ox-LDL, while ox-LDL reduction correlated with PCSK9 and sNOX2-dp delta. In vitro study demonstrated that wPLTs resuspended in plasma from HeFH after PCSK9i treatment induced lower PA and sNOX2-dp release than those obtained using plasma before PCSK9i treatment. This reduction was vanished by adding ox-LDL. ox-LDL-induced PA was blunted by CD36, LOX1, and NOX2 inhibition. Conclusions: PCSK9i treatment reduces PA modulating NOX2 activity and in turn ox-LDL formation in HeFH patients.

Deintensification or No Statin Treatment Is Associated With Higher Mortality in Patients With Ischemic Stroke or Transient Ischemic Attack

Background and Purpose: Practice guidelines recommend that most patients receive moderate- or high-potency statins after ischemic stroke or transient ischemic attack (TIA) of atherosclerotic origin. We tested the association of different patterns of potency for prescribed statin therapy—assessed before admission and at hospital discharge for ischemic stroke or TIA—on mortality in a large, nationwide sample of US Veterans. Methods: The study population included patients with an ischemic stroke or TIA occurring during 2011 at any of the 134 Veterans Health Administration facilities. We used electronic outpatient pharmacy files to identify statin dose at hospital admission and within 7 days after hospital discharge. We categorized statin dosing as low, moderate, or high potency; moderate or high potency was considered at goal. We created 6 mutually exclusive groups to reflect patterns of statin potency from hospital admission to discharge: goal to goal, low to goal, goal to low or goal to none (deintensification), none to none, none to low, and low to low. We used logistic regression to compare 30-day and 1-year mortality across statin potency groups. Results: The population included 9380 predominately White (71.1%) men (96.3%) who were hospitalized for stroke or TIA. In this sample, 34.1% of patients (n=3194) were discharged off a statin medication. Deintensification occurred in 14.0% of patients (n=1312) and none to none in 20.5% (n=1924). Deintensification and none to none were associated with a higher odds of mortality as compared with goal to goal (adjusted odds ratio 1-year mortality: deintensification versus goal to goal, 1.26 [95% CI, 1.02–1.57]; none to none versus goal to goal, 1.59 [95% CI, 1.30–1.93]). Adjustments for differences in baseline characteristics using propensity weighted scores demonstrated similar results. Conclusions: Underutilization of statins, including no treatment or underdosing after stroke (deintensification), was observed in approximately one-third of veterans with ischemic stroke or TIA and was associated with higher mortality when compared with patients who were at goal for statin prescription dosing.

Comparative effect of physical exercise versus statins on improving arterial stiffness in patients with high cardiometabolic risk: A network meta-analysis

Background The comparative analysis of the effect of several doses of statins against different intensities of physical exercise on arterial stiffness (a measure of cardiovascular risk) could shed light for clinicians on which method is most effective in preventing cardiovascular disease (CVD) and be used to inform shared decision-making between doctors and patients. This study was aimed at analyzing the effect, in high cardiometabolic risk patients, of different statins doses and exercise intensities on arterial stiffness (a measure of cardiovascular risk) by integrating all available direct and indirect evidence in network meta-analyses. Methods and findings We systematically searched MEDLINE, Embase, SPORTDiscus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science databases from their inception to February 28, 2020; for unpublished trials, we also searched ClinicalTrials.gov. We searched for studies concerning the effect of statins or physical exercise on arterial stiffness, measured by pulse wave velocity (PWV). For methodological quality assessment, Cochrane Collaboration’s tool for assessing risk of bias (RoB2) was used. A network geometry graph was used to assess the strength of the evidence. Comparative evaluation of the interventions effect was performed by conducting a standard pairwise meta-analysis and a network meta-analysis (NMA) for direct and indirect comparisons between interventions and control/nonintervention. A total of 22 studies were included in the analyses (18 randomized controlled trials (RCTs) and 4 nonrandomized experimental studies), including 1,307 patients with high cardiometabolic risk from Asia (3 studies), Oceania (2 studies), Europe (10 studies), North America (5 studies), and South America (2 studies). The overall risk of bias assessed with RoB2 was high in all included studies. For standard pairwise meta-analysis and NMA, high-intensity exercise versus control (mean difference (MD) −0.56; 95% CI: −1.01, −0.11; p = 0.015 and −0.62; 95% CI: −1.20, −0.04; p = 0.038, respectively) and moderate statin dose versus control (MD −0.80, 95% CI: −1.59, −0.01; p = 0.048 and −0.73, 95% CI: −1.30, −0.15; p = 0.014, respectively) showed significant MDs. When nonrandomized experimental studies were excluded, the effect on high-intensity exercise versus control and moderate statin dose versus was slightly modified. The main limitation of this study was that the magnitude of the effect of the exercise interventions could be underestimated due to regression toward the mean bias because the baseline cardiometabolic risk profile of patients in the physical exercise intervention trials was healthier than those in the statins ones; consequently, more modest improvements in physical exercise interventions compared to statins interventions can be expected. Additionally, we might consider as limitations the small study sizes, the heterogeneous patient groups, the focus on a proxy endpoint (PWV), and the high risk of bias. Conclusions In this NMA, we found that although many patients could benefit from statins for reducing CVD risk, our results support that, considering the beneficial effects of high-intensity exercise on arterial stiffness, it would be worthwhile to refocus our attention on this type of exercise as an effective tool for the prevention of CVD. Systematic review registration PROSPERO CRD42019123120.

Abstract 15913: Two-year Results of the Getting to an Improved Understanding of Low-density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD) Registry of Patients With Atherosclerotic Cardiovascular Disease (ASCVD)

Background: Atherosclerotic cardiovascular disease (ASCVD) treatment guidelines recommend intensive statin therapy and adding non-statin therapy if LDL-C ≥70 mg/dL. Methods: We designed the GOULD registry to assess lipid-lowering therapy (LLT) over time: At 120 U.S. centers, 5006 ASCVD patients on any (LLT) were enrolled in 1 of 3 cohorts: 1) currently on PCSK9 inhibitor (PCSK9i), 2) no PCSK9i and LDL-C ≥100 mg/dL, and 3) no PCSK9i and LDL-C 70-99 mg/dL. Results: Over the two years, only 16.8% had some type of LLT intensification, In the cohorts of patients with baseline LDL-C ≥ 100 and 70-99 mg/dL, LLT intensification was present in 21.9% and 14.3% respectively: statin dose was intensified in 6.1% and 6.1%, ezetimibe was added in 6.8% and 4.3% and PCSK9i was added in 6.3% and 2.2% respectively. Conversely, out of the total population, statins were discontinued in 246/4275 (5.8%), ezetimibe in 81/535 (15.1%), and PCSK9i in 47/544 (8.6%). At 24 months, 83.7% were on statin (43.4% high-intensity), with 14.2% on ezetimibe. Lipid panels were measured in 73% by 1 year and 84% by 2 years. Among Pts in the LDL-C ≥100 and 70-99 mg/dL cohorts, 18.6% and 30.4% achieved an LDL-C <70 mg/dL by 1 year, with little further change by 2 years: 21.3% and 33.5% respectively. In the PCSK9 cohort, 53.2% had LDL-C<70 mg/dl. Overall, only 31.7% had LDL-C <70 mg/dL at 2 years (an increase from 6.7% at baseline), while 25.0% had LDL-C >100 mg/dL. Conclusion: Of ASCVD patients with suboptimal LDL-C at baseline, even after 2 years of follow up, strikingly only 16% had LLT intensification, and thus most remained uncontrolled. Further intensive efforts are needed to achieve optimal LDL management in patients with ASCVD.

Reduced Protumorigenic Tumor-Associated Macrophages With Statin Use in Premalignant Human Lung Adenocarcinoma

Background Statins have anticancer properties by acting as competitive inhibitors of the mevalonate pathway. They also have anti-inflammatory activity, but their role in suppressing inflammation in a cancer context has not been investigated to date. Methods We have analyzed the relationship between statin use and tumor-associated macrophages (TAMs) in a cohort of 262 surgically resected primary human lung adenocarcinomas. TAMs were evaluated by multiplex immunostaining for the CD68 pan-TAM marker and the CD163 protumorigenic TAM marker followed by digital slide scanning and partially automated quantitation. Links between statin use and tumor stage, virulence, and cancer-specific survival were also investigated in a wider cohort of 958 lung adenocarcinoma cases. All statistical tests were two-sided. Results We found a statin dose-dependent reduction in protumorigenic TAMs (CD68+CD163+) in both stromal (P = .021) and parenchymal (P = .003) compartments within regions of in situ tumor growth, but this association was lost in invasive regions. No statistically significant relationship between statin use and tumor stage was observed, but there was a statin dose-dependent shift towards lower histological grade as assessed by growth pattern (P = .028). However, statin use was a predictor of slightly worse cancer-specific survival (P = .032), even after accounting for prognostic variables in a multivariable Cox proportional hazards survival model (hazard ratio = 1.38, 95% confidence interval = 1.04 to 1.84). Conclusions Statin use is associated with reduced numbers of protumorigenic TAMs within preinvasive lung adenocarcinoma and is related to reduced tumor invasiveness, suggesting a chemo-preventive effect in early tumor development. However, invasive disease is resistant to these effects, and no beneficial relationship between statin use and patient outcome is observed.

Percentage low-density lipoprotein-cholesterol response to a given statin dose is not fixed across the pre-treatment range: Real world evidence from clinical practice: Data from the ESC-EORP EUROASPIRE V Study

Aims Recent European guidelines recommend in patients with atherosclerotic cardiovascular disease to achieve a reduction of low-density lipoprotein-cholesterol of at least 50% if the baseline low-density lipoprotein-cholesterol level is between 1.8 and 3.5 mmol/L. Systematic reviews have associated a given statin/dose combination with a fixed percentage low-density lipoprotein-cholesterol response. Algorithms for detecting cases and estimating the prevalence of familial hypercholesterolaemia often rely on such fixed percentage reductions. Methods and results We used data from 915 coronary patients participating in the EUROASPIRE V study in whom atorvastatin or rosuvastatin therapy was initiated at hospital discharge and who were still using these drugs at the same dose at a follow-up visit 6 or more months later. Pre and on-treatment low-density lipoprotein-cholesterol levels were compared across the full low-density lipoprotein-cholesterol range. The prevalence of FH was estimated using the Dutch Lipid Clinic Network criteria, once using observed pre-treatment low-density lipoprotein-cholesterol and once using imputed pre-treatment low-density lipoprotein-cholesterol by following the common strategy of applying fixed correction factors to on-treatment low-density lipoprotein-cholesterol. Inter-individual variation in the low-density lipoprotein-cholesterol response to a fixed statin and dose was considerable, with a strong inverse relation of percentage reductions to pre-treatment low-density lipoprotein-cholesterol. The percentage low-density lipoprotein-cholesterol response was markedly lower at the left end of the pre-treatment low-density lipoprotein-cholesterol range especially for levels less than 3 mmol/L. The estimated prevalence of familial hypercholesterolaemia was 2% if using observed pre-treatment low-density lipoprotein-cholesterol and 10% when using imputed low-density lipoprotein-cholesterol. Conclusion The inter-individual variation in the percentage low-density lipoprotein-cholesterol response to a given dose of a statin is largely dependent on the pre-treatment level: the lower the pre-treatment low-density lipoprotein-cholesterol level the smaller the percentage low-density lipoprotein-cholesterol reduction. The use of uniform correction factors to estimate pre-treatment low-density lipoprotein-cholesterol is not justified.

Preadmission Statin Use and 90-day Mortality in the Critically Ill

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background This study aimed to examine the association between preadmission statin use and 90-day mortality in critically ill patients and to investigate whether this association differed according to statin type and dose. We hypothesized that preadmission statin use was associated with lower 90-day mortality. Methods This retrospective cohort study analyzed the medical records of all adult patients admitted to the intensive care unit in a single tertiary academic hospital between January 2012 and December 2017. Data including preadmission statin use, statin subtype, and daily dosage were collected, and the associations between these variables and 90-day mortality after intensive care unit admission were examined. The primary endpoint was 90-day mortality. Results A total of 24,928 patients (7,396 statin users and 17,532 non–statin users) were included. After propensity score matching, 5,354 statin users and 7,758 non–statin users were finally included. The 90-day mortality rate was significantly higher in non–statin users (918 of 7,758; 11.8%) than in statin users (455 of 5,354; 8.5%; P &lt; 0.001). In Cox regression analysis, the 90-day mortality rate was lower among statin users than among non–statin users (hazard ratio: 0.70, 95% CI: 0.63 to 0.79; P &lt; 0.001). Rosuvastatin use was associated with 42% lower 90-day mortality (hazard ratio: 0.58, 95% CI: 0.47 to 0.72; P &lt; 0.001). There were no specific significant differences in the association between daily statin dose and 90-day mortality. In competing risk analysis, the risk of noncardiovascular 90-day mortality in statin users was 32% lower than that in non–statin users (hazard ratio: 0.68, 95% CI: 0.60 to 0.78; P &lt; 0.001). Meanwhile, cardiovascular 90-day mortality was not significantly associated with statin use. Conclusions Preadmission statin use was associated with a lower 90-day mortality. This association was more evident in the rosuvastatin group and with noncardiovascular 90-day mortality; no differences were seen according to daily dosage intensity.