Inflammation and Cholesterol as Predictors of Cardiovascular Events Among 13 970 Contemporary High-Risk Patients With Statin Intolerance.

BACKGROUND: Among patients treated with statin therapy to guideline-recommended cholesterol levels, residual inflammatory risk assessed by high-sensitivity C-reactive protein (hsCRP) is at least as strong a predictor of future cardiovascular events as is residual risk assessed by low-density lipoprotein cholesterol (LDLC). Whether these relationships are present among statin-intolerant patients with higher LDLC levels is uncertain but has implications for the choice of preventive therapies, including bempedoic acid, an agent that reduces both LDLC and hsCRP. METHODS: The multinational CLEAR-Outcomes trial (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen Outcomes Trial) randomly allocated 13 970 statin-intolerant patients to 180 mg of oral bempedoic acid daily or matching placebo and followed them for a 4-component composite of incident myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and for all-cause mortality. Quartiles of increasing baseline hsCRP and LDLC were assessed as predictors of future adverse events after adjustment for traditional risk factors and randomized treatment assignment. RESULTS: Compared with placebo, bempedoic acid reduced median hsCRP by 21.6% and mean LDLC levels by 21.1% at 6 months. Baseline hsCRP was significantly associated with the primary composite end point of major cardiovascular events (highest versus lowest hsCRP quartile; hazard ratio [HR], 1.43 [95% CI, 1.24-1.65]), cardiovascular mortality (HR, 2.00 [95% CI, 1.53-2.61]), and all-cause mortality (HR, 2.21 [95% CI, 1.79-2.73]). By contrast, the relationship of baseline LDLC quartile (highest versus lowest) to future events was smaller in magnitude for the primary composite cardiovascular end point (HR, 1.19 [95% CI, 1.04-1.37]) and neutral for cardiovascular mortality (HR, 0.90 [95% CI, 0.70-1.17]) and all-cause mortality (HR, 0.95 [95% CI, 0.78-1.16]). Risks were high for those with elevated hsCRP irrespective of LDLC level. Bempedoic acid demonstrated similar efficacy in reducing cardiovascular events across all levels of hsCRP and LDLC. CONCLUSIONS: Among contemporary statin-intolerant patients, inflammation assessed by hsCRP predicted risk for future cardiovascular events and death more strongly than hyperlipidemia assessed by LDLC. Compared with placebo, bempedoic acid had similar efficacy for reducing cardiovascular risk across hsCRP and LDLC strata. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02993406.

Short-term effects of gastric bypass versus sleeve gastrectomy on high LDL cholesterol: The BASALTO randomized clinical trial.

BACKGROUND: There has been a substantial increase in the use of laparoscopic sleeve gastrectomy (SG) to treat morbid obesity despite observational evidence demonstrating the superiority of Roux-en-Y gastric bypass (RYGB) for reducing low-density lipoprotein (LDL) cholesterol. The main aim was to ascertain whether high LDL cholesterol levels should be considered when selecting the most appropriate surgical procedure for each patient (RYGB or SG). METHODS: In this single-center, randomized clinical trial using intention-to-treat analysis, 38 patients with severe obesity and elevated levels of LDL cholesterol were randomly assigned to undergo RYGB or SG. The primary outcome was LDL cholesterol remission at 12 months, defined as LDL cholesterol < 3.36 nmol/l without lipid-lowering medications. Secondary outcomes included changes in weight, other comorbidities, qualitative lipoprotein traits, cholesterol esters, glycoproteins, cholesterol absorption and synthesis metabolites and complications. RESULTS: Intention-to-treat analysis revealed that LDL cholesterol remission occurred in 66.6% of RYGB patients compared to 27.8% of SG patients (p = 0.019). Among patients completing follow-up, RYGB demonstrated superior remission (80.0% vs. 29.4%, p = 0.005). Exclusive benefits of RYGB included a reduction in large, medium, and small LDL particles. Cholesterol absorption markers showed differential behavior after both techniques: campesterol (Δ -15.2 µg/mg, 95% CI -30.2 to -0.1) decreased after RYGB, and sitosterol (Δ 21.1 µg/mg, 95% CI 0.9 to 41.2), cholestanol (Δ 30.6 µg/mg, 95% CI 14.8 to 57.9) and campesterol (Δ 18.4 µg/mg, 95% CI 4.4 to 32.3) increased after SG. No differences in weight loss, cholesterol esters, glycoproteins, cholesterol synthesis metabolites or postoperative complications were observed between techniques. CONCLUSION: In conclusion, RYGB is superior to SG in terms of short-term of high LDL cholesterol remission. Furthermore, RYGB also led to a greater improvement in lipoprotein parameters that confer an atherogenic profile. Therefore, the presence of elevated levels of LDL cholesterol should be considered when determining the optimal bariatric surgery procedure for each patient. TRIAL REGISTRATION: Clinicaltrials.gov number, NCT03975478).

Beyond 10-Year Risk: A Cost-Effectiveness Analysis of Statins for the Primary Prevention of Cardiovascular Disease.

BACKGROUND: Cholesterol guidelines typically prioritize primary prevention statin therapy on the basis of 10-year risk of cardiovascular disease. The advent of generic pricing may justify expansion of statin eligibility. Moreover, 10-year risk may not be the optimal approach for statin prioritization. We estimated the cost-effectiveness of expanding preventive statin eligibility and evaluated novel approaches to prioritization from a Scottish health sector perspective. METHODS: A computer simulation model predicted long-term health and cost outcomes in Scottish adults ≥40 years of age. Epidemiologic analysis was completed using the Scottish Heart Health Extended Cohort, Scottish Morbidity Records, and National Records of Scotland. A simulation cohort was constructed with data from the Scottish Health Survey 2011 and contemporary population estimates. Treatment and cost inputs were derived from published literature and health service cost data. The main outcome measure was the lifetime incremental cost-effectiveness ratio, evaluated as cost (2020 GBP) per quality-adjusted life-year (QALY) gained. Three approaches to statin prioritization were analyzed: 10-year risk scoring using the ASSIGN score, age-stratified risk thresholds to increase treatment rates in younger individuals, and absolute risk reduction (ARR)-guided therapy to increase treatment rates in individuals with elevated cholesterol levels. For each approach, 2 policies were considered: treating the same number of individuals as those with an ASSIGN score ≥20% (age-stratified risk threshold 20, ARR 20) and treating the same number of individuals as those with an ASSIGN score ≥10% (age-stratified risk threshold 10, ARR 10). RESULTS: Compared with an ASSIGN score ≥20%, reducing the risk threshold for statin initiation to 10% expanded eligibility from 804 000 (32% of adults ≥40 years of age without CVD) to 1 445 500 individuals (58%). This policy would be cost-effective (incremental cost-effectiveness ratio, £12 300/QALY [95% CI, £7690/QALY-£26 500/QALY]). Incremental to an ASSIGN score ≥20%, ARR 20 produced ≈8800 QALYs and was cost-effective (£7050/QALY [95% CI, £4560/QALY-£10 700/QALY]). Incremental to an ASSIGN score ≥10%, ARR 10 produced ≈7950 QALYs and was cost-effective (£11 700/QALY [95% CI, £9250/QALY-£16 900/QALY]). Both age-stratified risk threshold strategies were dominated (ie, more expensive and less effective than alternative treatment strategies). CONCLUSIONS: Generic pricing has rendered preventive statin therapy cost-effective for many adults. ARR-guided therapy is more effective than 10-year risk scoring and is cost-effective.

Randomized, Placebo-Controlled Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Lecithin Cholesterol Acyltransferase in Acute ST-Segment-Elevation Myocardial Infarction: Results of REAL-TIMI 63B.

BACKGROUND: High-density lipoprotein plays a key role in reverse cholesterol transport. In addition, high-density lipoprotein particles may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin-cholesterol acyltransferase is a rate-limiting enzyme in reverse cholesterol transport. MEDI6012 is a recombinant human lecithin-cholesterol acyltransferase that increases high-density lipoprotein cholesterol. Administration of lecithin-cholesterol acyltransferase has the potential to reduce infarct size and regress coronary plaque in acute ST-segment-elevation myocardial infarction. METHODS: REAL-TIMI 63B (A Randomized, Placebo­controlled Phase 2b Study to Evaluate the Safety and Efficacy of MEDI6012 in Acute ST Elevation Myocardial Infarction) was a phase 2B multinational, placebo-controlled, randomized trial. Patients with ST-segment-elevation myocardial infarction within 6 hours of symptom onset and planned for percutaneous intervention were randomly assigned 2:1 to MEDI6012 (2- or 6-dose regimen) or placebo and followed for 12 weeks. The primary outcome was infarct size as a percentage of left ventricular mass by cardiac MRI at 10 to 12 weeks, with the primary analysis in patients with TIMI Flow Grade 0 to 1 before percutaneous intervention who received at least 2 doses of MEDI6012. The secondary outcome was change in noncalcified plaque volume on coronary computed tomographic angiography from baseline to 10 to 12 weeks with the primary analysis in patients who received all 6 doses of MEDI6012. RESULTS: A total of 593 patients were randomly assigned. Patients were a median of 62 years old, 77.9% male, and 95.8% statin naive. Median time from symptom onset to randomization was 146 (interquartile range [IQR], 103-221) minutes and from hospitalization to randomization was 12.7 (IQR, 6.6-24.0) minutes, and the first dose of drug was administered a median of 8 (IQR, 3-13) minutes before percutaneous intervention. The index myocardial infarction was anterior in 69.6% and TIMI Flow Grade 0 to 1 in 65.1% of patients. At 12 weeks, infarct size did not differ between treatment groups (MEDI6012: 9.71%, IQR 4.79-16.38; placebo: 10.48%, [IQR, 4.92-16.61], 1-sided P=0.79. There was also no difference in noncalcified plaque volume (geometric mean ratio, 0.96 [95% CI, NA-1.10], 1-sided P=0.30). There was no significant difference in treatment emergent serious adverse events. CONCLUSIONS: Administration of MEDI6012 in patients with acute ST-segment-elevation myocardial infarction did not result in a significant reduction in infarct size or noncalcified plaque volume at 12 weeks. MEDI6012 was well tolerated with no excess in overall serious adverse events. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03578809.

More Than 50 Percent Reduction in LDL Cholesterol in Patients With Target LDL <70 mg/dL After a Stroke.

BACKGROUND: Whether a strategy to target an LDL (low-density lipoprotein) cholesterol <70 mg/dL is more effective when LDL is reduced >50% from baseline rather than <50% from baseline has not been investigated. METHODS: The Treat Stroke to Target trial was conducted in France and South Korea in 61 sites between March 2010 and December 2018. Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned to a target LDL cholesterol of <70 mg/dL or 100±10 mg/dL, using statin and/or ezetimibe as needed. We used the results of repeated LDL measurements (median, 5 [2-6] per patient) during 3.9 years (interquartile range, 2.1-6.8) of follow-up. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization, and vascular death. Cox regression model including lipid-lowering therapy as a time-varying variable, after adjustment for randomization strategy, age, sex, index event (stroke or transient ischemic attack), and time since the index event. RESULTS: Among 2860 patients enrolled, patients in the lower target group who had >50% LDL cholesterol reduction from baseline during the trial had a higher baseline LDL cholesterol and a lower LDL cholesterol achieved as compared to patients who had <50% LDL cholesterol reduction (155±32 and 62 mg/dL versus 121±34 and 74 mg/dL, respectively, P<0.001 for both). In the <70 mg/dL target group, patients with >50% LDL reduction had a significant reduction in the primary outcome as compared to the higher target group (hazard ratio, 0.61 [95% CI, 0.43-0.88]; P=0.007) and patients with <50% LDL reduction from baseline had little reduction (hazard ratio, 0.96 [95% CI, 0.73-1.26]; P=0.75). CONCLUSIONS: In this post hoc analysis of the TST trial, targeting an LDL cholesterol of <70 mg/dL reduced the risk of primary outcome compared with 100±10 mg/dL provided LDL cholesterol reduction from baseline was superior to 50%, thereby suggesting that the magnitude of LDL cholesterol reduction was as important to consider as the target level to achieve. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01252875. URL: https://clinicaltrialsregister.eu; Unique identifier: EUDRACT2009-A01280-57.

Statin Intolerance: an Overview of US and International Guidance.

PURPOSE OF REVIEW: To review recent international and domestic definitions, considerations, and treatment algorithms for statin intolerance, and specifically, statin-associated muscle symptoms (SAMS). RECENT FINDINGS: Multiple organizations around the world have produced guidance documents to aid clinicians on managing statin intolerance. A common theme resides among all the guidance documents that most patients can tolerate statins. For those patients who cannot, healthcare teams need to evaluate, rechallenge, educate, and ensure adequate reduction of atherogenic lipoproteins. Statin therapy remains the cornerstone of lipid-lowering therapies to reduce atherosclerotic cardiovascular disease (ASCVD) and reduce mortality and morbidity. The common theme throughout all these guidance documents is the importance of statin therapy to reduce ASCVD and continual adherence to treatment. Because adverse events occur and inhibit patients from achieving adequate lowering of their atherogenic lipoproteins, trial and rechallenge of statin therapy, as well as addition of non-statin therapies, especially in high-risk patients, is also undisputed. The main differences stem from laboratory monitoring and the classification of the severity of the adverse effect. Future research should focus on consistently diagnosing SAMS so that these patients can be easily identified in the electronic health records.

Role of Omega-3 Fatty Acids in Cardiovascular Disease: the Debate Continues.

PURPOSE OF REVIEW: The omega-3 fatty acids (n3-FAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have recently undergone testing for their ability to reduce residual cardiovascular (CV) risk among statin-treated subjects. The outcome trials have yielded highly inconsistent results, perhaps attributable to variations in dosage, formulation, and composition. In particular, CV trials using icosapent ethyl (IPE), a highly purified ethyl ester of EPA, reproducibly reduced CV events and progression of atherosclerosis compared with mixed EPA/DHA treatments. This review summarizes the mechanistic evidence for differences among n3-FAs on the development and manifestations of atherothrombotic disease. RECENT FINDINGS: Large randomized clinical trials with n3-FAs have produced discordant outcomes despite similar patient profiles, doses, and triglyceride (TG)-lowering effects. A large, randomized trial with IPE, a prescription EPA only formulation, showed robust reduction in CV events in statin treated patients in a manner proportional to achieved blood EPA concentrations. Multiple trials using mixed EPA/DHA formulations have not shown such benefits, despite similar TG lowering. These inconsistencies have inspired investigations into mechanistic differences among n3-FAs, as EPA and DHA have distinct membrane interactions, metabolic products, effects on cholesterol efflux, antioxidant properties, and tissue distribution. EPA maintains normal membrane cholesterol distribution, enhances endothelial function, and in combination with statins improves features implicated in plaque stability and reduces lipid content of plaques. Insights into reductions in residual CV risk have emerged from clinical trials using different formulations of n3-FAs. Among high-risk patients on contemporary care, mixed n3-FA formulations showed no reduction in CV events. The distinct benefits of IPE in multiple trials may arise from pleiotropic actions that correlate with on-treatment EPA levels beyond TG-lowering. These effects include altered platelet function, inflammation, cholesterol distribution, and endothelial dysfunction. Elucidating such mechanisms of vascular protection for EPA may lead to new interventions for atherosclerosis, a disease that continues to expand worldwide.

Prescribing statin therapy in physically (in)active individuals vs prescribing physical activity in statin-treated patients: A four-scenario practical approach.

Statins are among the most commonly prescribed medications worldwide. Statin-associated muscle symptoms (SAMS) represent a frequent statin-related adverse effect associated with statin discontinuation and increased cardiovascular disease (CVD) events. Emerging evidence indicate that the majority of SAMS might not be actually caused by statins, and the nocebo/drucebo effect (i.e. adverse effects caused by negative expectations) might also explain SAMS. Physical activity (PA) is a cornerstone in the management of CVD risk. However, evidence of increased creatine-kinase levels in statin-treated athletes exposed to a marathon has been generalized, at least to some extent, to the general population and other types of PA. This generalization is likely inappropriate and might induce fear around PA in statin users. In addition, the guidelines for lipid management focus on aerobic PA while the potential of reducing sedentary behavior and undertaking resistance training have been overlooked. The aim of this report is to provide a novel proposal for the concurrent prescription of statin therapy and PA addressing the most common and clinically relevant scenarios by simultaneously considering the different stages of statin therapy and the history of PA. These scenarios include i) statin therapy initiation in physically inactive patients, ii) PA/exercise initiation in statin-treated patients, iii) statin therapy initiation in physically active patients, and iv) statin therapy in athletes and very active individuals performing SAMS-risky activities.

Neutral effect of SGLT2 inhibitors on lipoprotein metabolism: From clinical evidence to molecular mechanisms.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective, well-tolerated, and safe glucose-lowering compounds for patients with type 2 diabetes mellitus (T2DM). SGLT2i benefit encompasses protection from heart and kidney failure, independently of the presence of diabetes. In addition, SGLT2i consistently reduce the risk of hospitalization for heart failure and, although with some heterogeneity between specific members of the class, favourably affect the risk of cardiovascular outcomes. The molecular mechanisms underlying the cardiovascular favourable effect are not fully clarified. Studies testing the efficacy of SGLT2i in human cohorts and experimental models of atherosclerotic cardiovascular disease (ASCVD) have reported significant differences in circulating levels and composition of lipoprotein classes. In randomized clinical trials, small but significant increases in low-density lipoprotein cholesterol (LDL-C) levels have been observed, with a still undefined clinical significance; on the other hand, favourable (although modest) effects on high-density lipoprotein cholesterol (HDL-C) and triglycerides have been reported. At the molecular level, glycosuria may promote a starving-like state that ultimately leads to a metabolic improvement through the mobilization of fatty acids from the adipose tissue and their oxidation for the production of ketone bodies. This, however, may also fuel hepatic cholesterol synthesis, thus inhibiting atherogenic lipoprotein uptake from the liver. Long-term studies collecting detailed information on lipid-lowering therapies at baseline and during the trials with SGLT2i, as well as regularly monitoring lipid profiles are warranted to disentangle the potential implications of SGLT2i in modulating lipoprotein-mediated atherosclerotic cardiovascular risk.

Aspirin for the Primary Prevention of Cardiovascular Disease: Time for a Platelet-Guided Approach.

Aspirin protects against atherothrombosis while increasing the risk of major bleeding. Although it is widely used to prevent cardiovascular disease (CVD), its benefit does not outweigh its risk for primary CVD prevention in large population settings. The recent United States Preventive Services Task Force guidelines on aspirin use to prevent CVD reflect this clinical tradeoff as well as the persistent struggle to define a population that would benefit from prophylactic aspirin therapy. Past clinical trials of primary CVD prevention with aspirin have not included consideration of a biomarker relevant to aspirin's mechanism of action, platelet inhibition. This approach is at odds with the paradigm used in other key areas of pharmacological CVD prevention, including antihypertensive and statin therapy, which combine cardiovascular risk assessment with the measurement of mechanistic biomarkers (eg, blood pressure and LDL [low-density lipoprotein]-cholesterol). Reliable methods for quantifying platelet activity, including light transmission aggregometry and platelet transcriptomics, exist and should be considered to identify individuals at elevated cardiovascular risk due to a hyperreactive platelet phenotype. Therefore, we propose a new, platelet-guided approach to the study of prophylactic aspirin therapy. We think that this new approach will reveal a population with hyperreactive platelets who will benefit most from primary CVD prevention with aspirin and usher in a new era of precision-guided antiplatelet therapy.

Factors affecting the effectiveness of the physical activity counselling intervention implemented in primary health care in adults with type 2 diabetes.

BACKGROUND: Type 2 diabetes (T2D) has become a major public health threat; physical inactivity and obesity are both independent risk factors. Increasing daily physical activity (PA) significantly benefits treatment. Individual PA counselling is helpful for people with T2D, especially those with previous inactivity or with diabetes complications. This study evaluated factors contributing to effectiveness of PA counselling in primary health care (PHC) patients with T2D in a real-world setting and using data elicited from electronic health records (EHRs). METHODS: All patients with T2D were offered the opportunity to participate in a PA program organized as part of basic PHC services in the Siun sote region in North Karelia, Finland, from October 2016 to December 2018. The study population consists of patients aged 19 to 87 years (n = 546). During the intervention information on possible other factors in addition to age and sex influencing the intervention effect such as amount of counselling sessions, changes in PA and patients´ motivation was gathered. Changes in the participants' PA activity was generated by following the predefined rules from patient records and by assessing the descriptive documentation of activity patterns. The patients' motivation level was assessed using a Likert scale. RESULTS: Over 60% of participants who attended PA counselling more than three times increased their PA compared with 1% of participants with one counselling session. Of the whole intervention group, the participants experiencing the largest weight loss were those with an increased level of PA (-1.36 kg vs. -0.63 kg among those with no change in PA). Age, sex, and baseline motivation did not affect the change the PA nor the main intervention outcomes. CONCLUSIONS: Patients' compliance with the intervention was reflected in the number of PA counselling sessions attended which in turn was seen as increased levels of PA as well as better treatment outcomes. In the implementation of lifestyle counselling interventions attention should be paid on sufficient amount and frequency of counselling sessions. The individually tailored PA counselling provided in PHC has similar effects regardless of sex and age.

Short-term safety and efficacy of escalating doses of atorvastatin for dyslipidemia in children with predialysis chronic kidney disease stage 2-5.

BACKGROUND: Dyslipidemia is a potentially modifiable risk factor in patients with chronic kidney disease (CKD). Information on the safety and efficacy of statins in pediatric CKD is limited. METHODS: Patients with CKD stage 2-5 and aged 5-18 years with low-density lipoprotein cholesterol (LDL-C) > 130 mg/dL and/or non-high-density lipoprotein cholesterol (non-HDL-C) > 145 mg/dL were enrolled from September 2019 to February 2021. All patients were administered atorvastatin 10 mg/day, which was escalated to 20 mg/day if LDL-C remained > 100 mg/dL and/or non-HDL-C > 120 mg/dL at 12 weeks. Proportion of patients achieving target lipid levels (LDL-C ≤ 100 mg/dL and non-HDL-C ≤ 120 mg/dL) and adverse events were assessed at 24 weeks. RESULTS: Of 31 patients enrolled, target lipid levels were achieved in 45.2% (95% CI 27.8-63.7%) at 24 weeks; 22 patients required dose escalation to 20 mg at 12 weeks. There was no difference in median lipid level reduction with 10 (n = 9) versus 20 mg/day (n = 22, P = 0.3). Higher baseline LDL-C (OR 1.06, 95% CI 1.00-1.11) and older age (OR 36.5, 95% CI 2.57-519.14) were independent predictors of failure to achieve target lipid levels with 10 mg/day atorvastatin. None had persistent rise in AST/ALT > 3 times upper normal limit (UNL) or CPK > 10 times UNL. No differences were noted in adverse events due to atorvastatin 10 or 20 mg/day. CONCLUSION: Atorvastatin (10-20 mg/day) administered for 24 weeks was safe and effectively reduced LDL-C and non-HDL-C in children with CKD stages 2-5. Patients with higher baseline LDL-C required higher doses to achieve the target. A higher resolution version of the Graphical abstract is available as Supplementary information.

Effects of a dietary intervention with Mediterranean vs lacto-ovo vegetarian diets on HDL function: Results from the CARDIVEG study.

BACKGROUND AND AIM: HDL-cholesterol efflux capacity (CEC) has been shown to be a better cardiovascular (CVD) risk marker than serum HDL concentration. Several foods and nutrients have been shown to improve HDL functions, however no effective dietetic nor pharmacological strategy is available to increase CEC. This study aims to evaluate the possible effect of Mediterranean diet (MD) and lacto-ovo-vegetarian diet (VD) on HDL function in a group of clinically healthy subjects at low-to-moderate CVD risk. METHODS AND RESULTS: Thirty apparently healthy subjects with a low-to-moderate cardiovascular risk profile (21 F; mean age: 51.3 ± 9.7 years) were randomly assigned to a 3-month MD or VD diet and then crossed. Participants on VD showed a reduction in total HDL CEC by 8.99% (p < 0.001) as well as a reduction in ABCA1 mediated-CEC by 18.62% (p < 0.001) compared to participants on MD. Regarding CEC mediated by aqueous diffusion, no significant changes were observed after treatment with either diet. Finally, a significant positive association between CEC mediated by the ABCA1 transporter and adiponectin was found (r = 0.462; p = 0.010). CONCLUSION: The results of this study suggest that HDL activity in promoting cholesterol efflux and thereby reducing the concentration of pro-atherogenic lipoproteins was more effective in participants undergoing MD than VD. Based on these findings, the MD could be considered a better therapeutic strategy for cardiovascular prevention than VD. CLINICAL TRIAL REGISTRATION URL: http://www. CLINICALTRIALS: gov. Unique identifier: NCT02641834.

Bempedoic Acid: A Contemporary Review of Its Pharmacology, Efficacy, and Safety Profile, Including Recent Data from the CLEAR Outcomes Clinical Trial.

PURPOSE OF REVIEW: To provide an updated review of bempedoic acid's clinical application in lowering LDL-C in the setting of statin intolerance and the recent findings in the CLEAR Outcomes trial as well as summarize and synthesize the current state of knowledge regarding bempedoic acid while providing an in-depth analysis of the drug's pharmacological properties, mechanism of action, clinical trials, safety, and efficacy. RECENT FINDINGS: The CLEAR Outcomes trial has provided evidence to support bempedoic acid as a viable alternative to statins for the primary and secondary prevention of cardiovascular disease. Bempedoic acid is a promising treatment option for patients with hypercholesterolemia who are unable to tolerate statin therapy or require additional LDL-C reduction in the treatment of cardiovascular disease, with the newest lipid-lowering cardiovascular outcomes trials expanding on their generalizability particularly in the inclusion of women.

Alpha-Linolenic Acid and Cardiovascular Events: A Narrative Review.

Cardiovascular diseases (CVDs) represent the leading cause of global mortality with 1.7 million deaths a year. One of the alternative systems to drug therapy to minimize the risk of CVDs is represented by alpha-linolenic acid (ALA), an essential fatty acid of the omega-3 series, known for its cholesterol-lowering effect. The main purpose of this review is to analyze the effects of ALA and investigate the relevant omega-6/omega-3 ratio in order to maintain functionally beneficial effects. Concerning the lipid-lowering preventive effects, ALA may favorably affect the values of LDL-C and triglycerides in both adult and pediatric populations. Furthermore, ALA has shown protective effects against hypertension, contributing to balancing blood pressure through customary diet. According to the 2009 EFSA statement, dietary ALA may contribute to reducing the risk of CVDs, thanks to anti-hypertensive, anti-atherosclerotic and cardioprotective effects.

Emerging Therapies for the Treatment of Atherosclerotic Cardiovascular Disease: From Bench to Bedside.

Primarily a consequence of sedentary lifestyle, atherosclerosis has already reached pandemic proportions, and with every year the burden of it is only increasing. As low-density lipoprotein cholesterol (LDL-C) represents a crucial factor in atherosclerosis formation and progression, stringent lipid-lowering therapy could conceivably be the key to preventing the unfavorable outcomes that arise as a consequence of atherosclerosis. The use of statins in lipid-lowering is often burdened by adverse events or is insufficient to prevent cardiovascular events as a monotherapy. Therefore, in the present review, the authors aimed to discuss the underlying mechanisms of dyslipidemia and associated atherosclerotic cardiovascular disease (ASCVD) and preclinical and clinical trials of novel therapeutic approaches to its treatment, some of which are still in the early stages of development. Apart from novel therapies, a novel change in perspective is needed. Specifically, the critical objective in the future management of ASCVD is to embrace emerging evidence in the field of atherosclerosis, because clinicians are often burden by common practice and personal experience, both of which have so far been shown to be futile in the setting of atherosclerosis.

Physicians' perceptions and beliefs on the current dyslipidemia management practices within Saudi Arabia.

Background: Limited reports addressing physicians' understanding of the various low-density lipoprotein cholesterol (LDL-C) targets/statin intensity required for treating the various dyslipidemia patient populations in Saudi Arabia are available. Therefore, the current study assessed the perceptions and beliefs of practicing clinicians in Saudi Arabia regarding the current practice for management of dyslipidemia and potential perceived barriers to adherence to lipid guidelines encountered in their regular clinical practice. Knowledge of different clinical practices and beliefs could have a positive impact on improving the quality of future care provided by physicians. Methods: A survey questionnaire was designed to assess physicians' familiarity, usage, and adherence to seven different international guidelines and used to evaluate the management of dyslipidemia, practice of patient treatment, and perceived obstacles to adhering to lipid guidelines related to specific patients, doctors, and practice issues. Results: A total of 467 physicians were recruited for the study: (1) 57.2% were primary care physicians (PCPs) and (2) 42.8% were specialists. About 90.8% of them followed lipid guidelines of which the most common set were based on those by the American College of Cardiology/American Heart Association. The most utilized risk assessment tool was the atherosclerotic cardiovascular disease (ASCVD) risk calculator. About 60% of the physicians set an LDL-C target for their patients based on a combination of patients' risk factors and lipid profiles. In all, 42.1% of the physicians chose not to change existing therapy among patients with dyslipidemia to attain a non-high-density lipoprotein goal with controlled LDL-C level. Atorvastatin accounted for the greatest percentage of primary and secondary prevention choices (71.9% and 69.6%, respectively). Rosuvastatin was mostly preferred by physicians for patients with familial hypercholesterolemia. About two-thirds of the physicians (77.9%) prescribed statins to diabetic patients aged 40-75 years. Statin intolerance was encountered by 62.9% of the physicians in ≤ 10% of patients by 62.9%. Therapeutic strategies included switching to an alternative statin (40.1%) followed by reducing the statin dose (35.3%). Ezetimibe was prescribed by most physicians (77.9%) as an add-on to statin if the LDL-C target was not achieved. Fibrate was most preferred by physicians (62.7%) for hypertriglyceremia treatment followed by statins (28.7% of the physicians). Sixty-six percent reported not using proprotein convertase subtilisin/kexin type 9 serine protease inhibitors in their clinical practice due to unavailability at their institute (51.8%), high costs (26.3%), and/or lack of knowledge (20.6%). Perceived barriers to guideline adherence identified by physicians were lack of familiarity and knowledge of the guidelines, patient non-adherence, medication costs, and lack of timely follow-up appointments and educational tools. Multiple similarities and differences were observed after comparisons were made between specialists and PCPs in terms of guideline preference, clinical practice, and perceived barriers. Conclusion: Different perceptions and attitudes among physicians in Saudi Arabia were found due to variable recommendations by international lipid guidelines. Perceived barriers that included the patient, physician, and practice were identified by physicians at multiple levels. Multiple challenges and different action gaps were observed when comparing specialists to PCPs. It is recommended that standardized practices be followed by clinicians in Saudi Arabia, and actions to address the outlined barriers are essential for optimizing health outcomes and ASCVD prevention.

Polypill: Benefits Seen for Stroke and Other Outcomes.

A polypill-type strategy for primary prevention was first published at the turn of the century and advised that a multi-ingredient pill applied to an adult population would prevent up to 80% of cardiovascular and stroke events. Such a pill should contain small doses of antihypertensives, lipid-lowering drugs, and some nutrients. The startling increase of the global stroke burden has led to a revival of this concept and the propagation of a population-based prevention strategy. Recent cardiovascular fixed-dose combination trials have shown a significant effect in reducing not only blood pressure and cholesterol levels but also in reducing cardiovascular and stroke events. In most of the studies, the study population was for secondary prevention and the total number of strokes was small. Nevertheless, it is now clear that a large proportion of primary prevention must take this path. It is especially promising when combined with community health workers interventions for modifying risk behavior. While a polypill-type approach seems most efficacious in underserved regions of high-income countries as well as in low- and middle-income countries, it seems to have a large overall effect in spite of some problems with nonadherence or potential side effects. It should be available and affordable for large target populations. Larger phase 4 studies are under way.

Does a History of Cancer Influence the Effectiveness of Statins on Outcomes After Stroke?

BACKGROUND: Evidence is growing on anticancer effects of statins. We investigated whether the effectiveness of treatment with statins after ischemic stroke on mortality is influenced by a history of cancer. METHODS: Analyses of 90-day survivors of ischemic stroke (2012-2016; 45 hospitals) using linked registry and administrative data. Dispense of statins within 90 days postdischarge was determined from pharmaceutical records. Participants were followed from 91 days postdischarge until death or June 30, 2018. History of cancer was determined from hospital data. Propensity score-adjusted Cox proportional hazards regression model was used to determine the association between being dispensed statins and survival. The influence of history of cancer on this association was assessed based on the concepts of (1) statistical interaction and (2) biological interaction using 3 indices: relative excess risk due to interaction>0, attributable proportion due to interaction >0, or synergy index >1. RESULTS: Among 9948 eligible participants (median age=72 years, 42% female), there were 1463 deaths. In adjusted analyses, there was no statistical interaction between being dispensed statins and history of cancer on mortality (P=0.156). However, being dispensed statins had a significant positive biological interaction with having a history of cancer on mortality: relative excess risk due to interaction, 2.80 (95% CI, 1.56-5.05), attributable proportion due to interaction, 0.45 (95% CI, 0.23-0.66), and synergy index, 2.14 (95% CI, 1.32-3.49). CONCLUSIONS: Treatment with statins after ischemic stroke may confer additional survival benefits for people who also have had cancer.

The role of statins in the prevention of preeclampsia.

Preeclampsia is a common hypertensive disorder of pregnancy associated with considerable neonatal and maternal morbidities and mortalities. However, the exact cause of preeclampsia remains unknown; it is generally accepted that abnormal placentation resulting in the release of soluble antiangiogenic factors, coupled with increased oxidative stress and inflammation, leads to systemic endothelial dysfunction and the clinical manifestations of the disease. Statins have been found to correct similar pathophysiological pathways that underlie the development of preeclampsia. Pravastatin, specifically, has been reported in various preclinical and clinical studies to reverse the pregnancy-specific angiogenic imbalance associated with preeclampsia, to restore global endothelial health, and to prevent oxidative and inflammatory injury. Human studies have found a favorable safety profile for pravastatin, and more recent evidence does not support the previous teratogenic concerns surrounding statins in pregnancy. With reassuring and positive findings from pilot studies and strong biological plausibility, statins should be investigated in large clinical randomized-controlled trials for the prevention of preeclampsia.