-
Cardiovascular Endocrinology &... Sep 2024Bempedoic acid (BA) has shown varied efficacy in managing hyperlipidemia. We conducted the most extensive up-to-date meta-analysis, the first to include recent studies... (Review)
Review
Efficacy and outcomes of bempedoic acid versus placebo in patients with hypercholesterolemia: an updated systematic review and meta-analysis of randomized controlled trials.
INTRODUCTION
Bempedoic acid (BA) has shown varied efficacy in managing hyperlipidemia. We conducted the most extensive up-to-date meta-analysis, the first to include recent studies by Nissen et al., which boast the largest sample size.
METHODS
Literature search was done on Medline, EMBASE, and Cochrane Library. The primary endpoint was a change in low-density lipoprotein-cholesterol (LDL-C) levels, while secondary endpoints encompassed changes in lipid parameters, clinical endpoints, and safety endpoints. The least-square mean (LSM) percent change was utilized for lipid changes, with statistical significance set at < 0.05.
RESULTS
This analysis included 12 randomized control trials with 22,249 participants. BA exhibited a substantial reduction in LDL-C levels [LSM % change, -24.34; 95% confidence interval (CI), -27.80 to -20.88; < 0.0001], total cholesterol levels (LSM % change, -16.62; 95% CI, -21.70 to -11.54; < 0.00001) and high-density lipoprotein-cholesterol (HDL-C) levels (LSM % change, -4.22; 95% CI, -5.51 to -2.92; < 0.00001) compared to the placebo.
CONCLUSIONS
BA significantly lowers LDL-C, total cholesterol, HDL-C, non-HDL-C, high sensitivity C reactive protein, and apolipoprotein levels.
PubMed: 38911912
DOI: 10.1097/XCE.0000000000000302 -
Clinical Medicine Insights. Cardiology 2024Cardiovascular illnesses (CVDs), particularly Coronary Artery Disease (CAD) and Ischemic Heart Disease (IHD), are major global health burdens, with a growing incidence...
Cardiovascular illnesses (CVDs), particularly Coronary Artery Disease (CAD) and Ischemic Heart Disease (IHD), are major global health burdens, with a growing incidence in Pakistan. The development of PCSK9 inhibitors offers encouraging advantages in lowering LDL cholesterol and lowering cardiovascular risk, even though conservative treatments are still essential. However, access to them is severely hampered by their high cost, especially in environments with little resources. The financial limitations and scarcity of healthcare resources while examining the difficulties in obtaining PCSK9 inhibitors in Pakistan is essential. In order to develop solutions for affordability and fair access, it emphasizes the urgent need for multi-stakeholder collaboration, including governmental action, healthcare sector involvement, and pharmaceutical company engagement. It also emphasizes the need for data-specific research and the use of PCSK9 inhibitors in conventional treatment protocols.
PubMed: 38911696
DOI: 10.1177/11795468241262648 -
Journal of Clinical Lipidology Mar 2024Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is an ultra-rare autosomal recessive disease characterized by very low HDL-C levels, corneal...
Longitudinal analysis of clinical and laboratory biomarkers in a patient with familial lecithin: Cholesterol acyltransferase deficiency (FLD) and accelerated eGFR decline: A case study.
Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is an ultra-rare autosomal recessive disease characterized by very low HDL-C levels, corneal opacity, anemia, and progressive renal disease. The rate and severity of renal disease are variable across FLD patients and the biomarkers and risk factors for disease progression are poorly understood. Here we report a 30 year-long comparative analysis of the clinical and laboratory biomarkers in an FLD patient with accelerated renal decline, who underwent 2 kidney and one liver transplantations. Results show that elevated TG and non-HDL-C levels may promote the formation of LpX and accelerate renal function decline, whereas markers of anemia may be early predictors. Conversely, corneal opacity progresses at a steady rate and does not correlate with lipid, hematologic, or renal biomarkers. Our study suggests that monitoring of markers of anemia may aid the early detection and timely management of kidney disease with conservative therapies. Furthermore, it suggests that controlling hypercholesterolemia and hypertriglyceridemia may help improve renal disease prognosis.
PubMed: 38910105
DOI: 10.1016/j.jacl.2024.03.002 -
Journal of Clinical Lipidology Apr 2024The International Atherosclerosis Society (IAS) published an evidence-informed guidance for familial hypercholesterolemia (FH) that provides both clinical and...
BACKGROUND
The International Atherosclerosis Society (IAS) published an evidence-informed guidance for familial hypercholesterolemia (FH) that provides both clinical and implementation recommendations. We reference examples of strategies from the literature to explore how these implementation recommendations can be tailored into implementation strategies at the local-level for stakeholders guided by a framework proposed by Sarkies and Jones.
METHODS
Four authors of the IAS guidance selected two published exemplar implementation recommendations for detection, management, and general implementation. Each recommendation was described as an implementation strategy using Proctor's guidance for specifying and reporting implementation strategies. It recommends reporting the actor (who), action (what), action-target (who is impacted), temporality (how often), and dose (how much) for each implementation strategy.
RESULTS
Detection: A centralized cascade testing model, mobilized nurses (actor) to relative's homes, after the diagnosis of the proband (temporality), once (dose) to consent, obtain a blood sample and health information (action) on relatives (action-target).
MANAGEMENT
A primary care initiative to improve FH management included an educational session (action) with clinicians (action-target), computer-based reminder message and message to patients to have their cholesterol screened once (dose) at a visit or outreach (temporality) by researchers (actor). General: A partnership between a statewide public pathology provider, local public hospital network, primary health network, government health ministry, and an academic university (actors) was established to implement a primary-tertiary shared care model (action) to improve the detection of FH (action-target).
CONCLUSIONS
We demonstrate that implementation recommendations can be specified and reported for different local contexts with examples on monitoring, evaluation, and sustainability in practice.
PubMed: 38910104
DOI: 10.1016/j.jacl.2024.03.010 -
American Journal of Preventive Medicine Jun 2024Herpes zoster increases stroke and myocardial infarction (MI) risk. The objective of this study is to evaluate the impact of live attenuated zoster vaccination on stroke...
INTRODUCTION
Herpes zoster increases stroke and myocardial infarction (MI) risk. The objective of this study is to evaluate the impact of live attenuated zoster vaccination on stroke and MI risk in patients at-risk for zoster including persons with hypertension, diabetes mellites, obesity, hypercholesterolemia, chronic kidney disease, chronic obstructive pulmonary disease, emphysema, asthma, and chronic liver disease.
METHODS
Retrospective cohort study utilizing continuous de-identified claims data from the IBM MarketScan® Commercial Claims and Encounters Database (collected from 2005-2018) containing data for 200 million commercially insured Americans. Participants included 27,093 adults vaccinated against zoster with at least 5 years continuous enrollment, age and sex-matched 1:5 with unvaccinated controls. Odds ratios, risk difference, and number needed to treat (NNT) evaluated the effect of vaccination on stroke and MI while controlling for relevant comorbidities.
RESULTS
Over five years, proportions of MI (1.29% vs 1.82%; p<0.05) and stroke (1.61% vs. 2.20%; p<0.05) were lower in vaccinated versus unvaccinated individuals respectively, controlling for age and sex, with greatest benefit for people with diabetes (stroke OR [95% Confidence Limits] 0.64 [0.58, 0.71], MI 0.63 [0.57, 0.71]). Although hypertension and chronic obstructive pulmonary disease (COPD) had highest odds of stroke and MI, vaccination still provided significant risk-reduction (Hypertension: stroke 0.75 [0.68, 0.83], MI 0.73 [0.65, 0.81]; COPD: stroke 0.75 [0.68, 0.83], MI 0.74 [0.66, 0.83]).
CONCLUSIONS
Live attenuated zoster vaccination is associated with lower risk stroke and MI in adults with at-risk comorbidities, controlling for age and sex. Vaccination may provide cardiovascular benefits beyond zoster prevention.
PubMed: 38909663
DOI: 10.1016/j.amepre.2024.06.018 -
BMC Medical Research Methodology Jun 2024Baseline imbalances have been identified in randomized trials of evolocumab and alirocumab. Our aim was to quantitatively assess (1) the presence of systematic baseline... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Baseline imbalances have been identified in randomized trials of evolocumab and alirocumab. Our aim was to quantitatively assess (1) the presence of systematic baseline differences, and (2) the relationship of baseline differences with effects on low-density lipoprotein-cholesterol (LDL-c) and clinical outcomes in the trials.
METHODS
We performed a meta-epidemiological study. PubMed, Embase, regulatory reports, ClinicalTrials.gov and company websites were searched for trials. Seven baseline characteristics (mean age, LDL-c, BMI, percentage males, diabetics, smokers, and hypertensives) and five outcomes (LDL-c, major adverse cardiac events, serious adverse events, any adverse events, all-cause mortality) were extracted. We calculated (1) range and distribution of baseline imbalances (sign-test), (2) pooled baseline differences and heterogeneity (meta-analysis), (3) differences in SDs around continuous variables (sign-test and pooling), and (4) the relationship of baseline differences with outcomes (meta-regression). The comparisons of PCSK9-inhibitor groups with either placebo or ezetimibe were analysed separately and combined.
RESULTS
We identified 43 trials with 63,193 participants. Baseline characteristics were frequently missing. Many trials showed small baseline imbalances, but some large imbalances. Only baseline BMI showed a statistically significant lower pooled mean for the drug versus placebo groups (MD -0.16; 95% CI -0.24 to -0.09). Heterogeneity in baseline imbalances was present in six placebo- and five ezetimibe-comparisons. Heterogeneity was statistically significant for BMI, males, diabetics and hypertensives in the combined comparisons. There was a statistically significant preponderance for larger SDs in the PCSK9-inhibitor versus control groups (sign-test age 0.014; LDL-c 0.014; BMI 0.049). Meta-regression showed clinically relevant relationships of baseline imbalances in age, BMI and diabetics with the risk of any adverse events and the risk of mortality. Two relationships were statistically significant: A higher mean BMI in the drug versus control group with a decreased risk of mortality (beta - 0.56; 95% CI -1.10 to -0.02), and a higher proportion of diabetics with an increased risk of any adverse events (beta 0.02; 95% 0.01 to 0.04).
CONCLUSIONS
Heterogeneous baseline imbalances and systematically different SDs were present in evolocumab and alirocumab trials, so study groups cannot be assumed to be comparable. These findings raise concerns about the design and conduct of the randomization procedures.
Topics: Humans; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Cholesterol, LDL; Male; Anticholesteremic Agents; Randomized Controlled Trials as Topic; Female; Treatment Outcome; Middle Aged; Hypercholesterolemia; PCSK9 Inhibitors; Aged; Proprotein Convertase 9
PubMed: 38909176
DOI: 10.1186/s12874-024-02260-z -
Journal of Clinical Lipidology May 2024Inclisiran, a small-interfering RNA enabling long-term inhibition of PCSK9 synthesis, demonstrates good safety and efficacy profile in clinical trials. Real-world data...
BACKGROUND
Inclisiran, a small-interfering RNA enabling long-term inhibition of PCSK9 synthesis, demonstrates good safety and efficacy profile in clinical trials. Real-world data on the potential to attain lipid-goals and reduce treatment gaps is lacking.
OBJECTIVES
To investigate the implementation of inclisiran in real-world clinical setting.
METHODS
Data from a nationwide healthcare organization on patients initiating inclisiran between 3/2022-11/2023. Patients' characteristics, lipid-lowering therapies, post-treatment reduction in low-density lipoprotein cholesterol (LDL-C), and attainment of treatment goals, were evaluated.
RESULTS
Inclisiran was initiated by 503 patients (57 % women; mean age 66±11 years). Cardiovascular disease was present in 54 %, and peak LDL-C levels >190 mg/dL documented in 64 %. Prior exposure to PCSK9 monoclonal antibodies was evident in 28 %. Lipid profile >2 months after filling first prescription, was available in 397 patients (347 with ≥2 injections). In patients treated by inclisiran only (n = 254), median LDL-C reduction from peak levels was 57 % (IQR, 48 %-67 %), and from pre-injection levels 40 % (19 %-54 %). In those with concomitant lipid-lowering therapies (n = 143), median LDL-C reduction from peak levels was 66 % (IQR, 55 %-73 %), and from pre-injection levels 46 % (23 %-59 %). LDL-C < 70 mg/dL was attained by 39 % and LDL-C < 55 mg/dL by 21.9 %. Of those treated with concomitant statin therapy, 38 % attained LDL-C < 55 mg/dL. Overall, 6.5 % discontinued inclisiran therapy after initial injection.
CONCLUSIONS
In real-world practice, inclisiran showed good efficacy in reducing LDL-C with high interindividual variability. However, attainment rates of lipid-goals were suboptimal due to limited use of combination lipid-lowering therapy and high-rates of severe hypercholesterolemia in our patient population cohort.
PubMed: 38908973
DOI: 10.1016/j.jacl.2024.05.003 -
Journal of Clinical Lipidology Apr 2024Cardiovascular (CV) risk scores identify individuals at higher long-term risk of CV events that may benefit from more aggressive preventive interventions.
BACKGROUND
Cardiovascular (CV) risk scores identify individuals at higher long-term risk of CV events that may benefit from more aggressive preventive interventions.
OBJECTIVE
To assess the association of CV-risk categories and criteria with long-term CV events.
METHODS
Observational cohort study between 2000-2019 on patients aged 40-80 years, followed by 14 primary care centers assisted by 1 hospital in Portugal. Follow-up began when electronic health records data allowed for CV-risk classification and dynamic reassessment per 2019 ESC/EAS Guidelines. Inclusion criteria required at least one appointment with a primary care physician within three years before follow-up initiation. We assessed the 10-year adjusted hazard-ratio of combined CV death and non-fatal Atherosclerotic Cardiovascular Disease (ASCVD) hospitalization, across SCORE risk categories and criteria, using Cox proportional hazards models adjusted for sex, age, competing comorbidities, and medication.
RESULTS
The study included 161 681 observations from 87 035 unique patients. During the observation period, 71 787 patients were classified as low/moderate, 51 476 as high and 38 418 as very-high CV-risk categories. In the very-high group, prevalent comorbidities were hypertension (69%), hypercholesterolemia (69%) and type 2 diabetes (61%), and 13% were hospitalized for ASCVD. The adjusted 10-year hazard ratio of the composite of CV death or ASCVD hospitalization was 2.10 (95% CI: 1.91-2.32) for high-risk and 3.56 (95% CI: 3.21-3.96) for very-high-risk patients (low-risk as reference).
CONCLUSION
Our study reinforces the prognostic relevance of CV-risk stratification for long-term prediction of CV death and ASCVD hospitalization in an unselected cohort, independently of sex, age, competing comorbidities and medication.
PubMed: 38908967
DOI: 10.1016/j.jacl.2024.04.002 -
BMJ Open Jun 2024In trials, subgroup analyses are used to examine whether treatment effects differ by important patient characteristics. However, which subgroups are most commonly... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
In trials, subgroup analyses are used to examine whether treatment effects differ by important patient characteristics. However, which subgroups are most commonly reported has not been comprehensively described.
DESIGN AND SETTINGS
Using a set of trials identified from the US clinical trials register (ClinicalTrials.gov), we describe every reported subgroup for a range of conditions and drug classes.
METHODS
We obtained trial characteristics from ClinicalTrials.gov via the Aggregate Analysis of ClinicalTrials.gov database. We subsequently obtained all corresponding PubMed-indexed papers and screened these for subgroup reporting. Tables and text for reported subgroups were extracted and standardised using Medical Subject Headings and WHO Anatomical Therapeutic Chemical codes. Via logistic and Poisson regression models we identified independent predictors of result reporting (any vs none) and subgroup reporting (any vs none and counts). We then summarised subgroup reporting by index condition and presented all subgroups for all trials via a web-based interactive heatmap (https://ihwph-hehta.shinyapps.io/subgroup_reporting_app/).
RESULTS
Among 2235 eligible trials, 23% (524 trials) reported subgroups. Follow-up time (OR, 95%CI: 1.13, 1.04-1.24), enrolment (per 10-fold increment, 3.48, 2.25-5.47), trial starting year (1.07, 1.03-1.11) and specific index conditions (eg, hypercholesterolaemia, hypertension, taking asthma as the reference, OR ranged from 0.15 to 10.44), predicted reporting, sponsoring source and number of arms did not. Results were similar on modelling any result reporting (except number of arms, 1.42, 1.15-1.74) and the total number of subgroups. Age (51%), gender (45%), racial group (28%) were the most frequently reported subgroups. Characteristics related to the index condition (severity/duration/types etc) were frequently reported (eg, 69% of myocardial infarction trials reported on its severity/duration/types). However, reporting on comorbidity/frailty (five trials) and mental health (four trials) was rare.
CONCLUSION
Other than age, sex, race ethnicity or geographic location and characteristics related to the index condition, information on variation in treatment effects is sparse.
PROSPERO REGISTRATION NUMBER
CRD42018048202.
Topics: Humans; Chronic Disease; Clinical Trials as Topic; Epidemiologic Studies; Research Design
PubMed: 38908852
DOI: 10.1136/bmjopen-2023-081315 -
Cardiovascular Drugs and Therapy Jun 2024Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the modulation of lipid metabolism as a critical negative regulator of hepatic low-density... (Review)
Review
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the modulation of lipid metabolism as a critical negative regulator of hepatic low-density lipoprotein receptor (LDLR) levels and circulating low-density lipoprotein (LDL) clearance. Numerous gain-of-function (GOF) mutations in PCSK9 have been identified as causing familial hypercholesterolemia (FH) by reducing LDLR levels, and loss-of-function (LOF) mutations associated with a hypercholesterolemia phenotype protective against atherosclerosis. PCSK9 represents an example of successful translational research resulting in the identification of PCSK9 as a major drug target for a lipid-lowering therapy. To explore the genetic constitution of PCSK9 and its biologic role, in this review, we summarize the current evidence of clinically significant PCSK9 genetic variants involved in lipid metabolism as well as emphasize the importance of PCSK9 inhibition for the improvement of cardiovascular outcomes by conducting a meta-analysis of the available data on the incidence of cardiovascular disease events.
PubMed: 38907775
DOI: 10.1007/s10557-024-07599-5