Cost-effectiveness of adding ezetimibe and/or PCSK9 inhibitors to high-dose statins for secondary prevention of cardiovascular disease in Chinese adults.

OBJECTIVES: The latest international guideline recommended the add-on therapy of ezetimibe and PCSK9 inhibitors in selected people for the secondary prevention of cardiovascular diseases (CVDs). However, it remains unclear whether these regimens fit the Chinese healthcare system economically. METHODS: Based on the Chinese context, this simulation study evaluated four therapeutic strategies including the high-dose statin-only group, ezetimibe plus statin group, PCSK9 inhibitors plus statin group, and PCSK9 inhibitors plus ezetimibe plus statin group. The team developed a Markov model to estimate the incremental cost-effectiveness ratio (ICER). With each 1-yr cycle, the simulation subjects could have nonfatal cardiovascular events (stroke and/or myocardial infarction) or death (vascular or nonvascular death event) with a follow-up duration of 20 yr. Cardiovascular risk reduction was gathered from a network meta-analysis, and cost and utility data were gathered from hospital databases and published research. RESULTS: For Chinese adults receiving high-dose statins for secondary prevention of CVDs, the ICER was US$68,910 per quality-adjusted life year (QALY) for adding PCSK9 inhibitors, US$20,242 per QALY for adding ezetimibe, US$51,552 per QALY for adding both drugs. Given a threshold of US$37,655 (three times of Chinese GDP), the probability of cost-effectiveness is 2.9 percent for adding PCSK9 inhibitors, 53.1 percent for adding ezetimibe, and 16.8 percent for adding both drugs. To meet the cost-effectiveness, an acquisition price reduction of PCSK9 inhibitors of 33.6 percent is necessary. CONCLUSION: In Chinese adults receiving high-dose statins for the secondary prevention of CVDs, adding ezetimibe is cost-effective compared to adding PCSK9 inhibitors and adding both drugs.

Trends of the Global Burden of Disease Attributable to Cannabis Use Disorder in 204 Countries and Territories, 1990-2019: Results from the Disease Burden Study 2019.

Cannabis is the fourth psychoactive substance to be legalized which are of far-reaching significance to the world. We analyzed data from the 2019 Global Burden of Disease Study (GBD) to estimate the incidence and prevalence of cannabis use disorder (CUD) and calculated the disease burden of CUD in 204 countries and territories and 21 regions over the past three decades. We reported disease burden due to CUD in terms of disability-adjusted life years (DALYs), age-standardized rate (ASR), estimated annual percentage change (EAPC), and analyzed associations between the burden of CUD and sociodemographic index (SDI) quintiles. Globally, the number of incidence cases of CUD was estimated to be increasing by 32.3% from 1990 to 2019 and males are nearly double higher than that of female. DALYs increase 38.6% from 1990. Young people aged 20-24 years old with cannabis use disorder have the highest DALYs in 2019, followed by those younger than 20 years old. India, Canada, USA, Qatar, Kenya, and high SDI quintile areas showed a high burden of disease. Nearly 200 million individuals are cannabis users worldwide, and CUD is a notable condition of GBD. The global cultivation of cannabis, rooted in different cultures, diversified access to cannabis, legalization in controversy, the promotion of medical cannabis, and many other factors promote the global cannabis industry is constantly updated and upgraded. It deserves more discussion in the future in terms of pathophysiological mechanisms, socioeconomics, law, and policy improvement. Supplementary Information: The online version contains supplementary material available at 10.1007/s11469-022-00999-4.

Glycated Haemoglobin A1c Variability Score Elicits Kidney Function Decline in Chinese People Living with Type 2 Diabetes.

Our aim was to investigate the association of glycated haemoglobin A1c (HbA1c) variability score (HVS) with estimated glomerular filtration rate (eGFR) slope in Chinese adults living with type 2 diabetes. This cohort study included adults with type 2 diabetes attending outpatient clinics between 2011 and 2019 from a large electronic medical record-based database of diabetes in China (WECODe). We estimated the individual-level visit-to-visit HbA1c variability using HVS, a proportion of changes in HbA1c of ≥0.5% (5.5 mmol/mol). We estimated the odds of people experiencing a rapid eGFR annual decline using a logistic regression and differences across HVS categories in the mean eGFR slope using a mixed-effect model. The analysis involved 2397 individuals and a median follow-up of 4.7 years. Compared with people with HVS ≤ 20%, those with HVS of 60% to 80% had 11% higher odds of experiencing rapid eGFR annual decline, with an extra eGFR decline of 0.93 mL/min/1.73 m2 per year on average; those with HVS > 80% showed 26% higher odds of experiencing a rapid eGFR annual decline, with an extra decline of 1.83 mL/min/1.73 m2 per year on average. Chinese adults with type 2 diabetes and HVS > 60% could experience a more rapid eGFR decline.

Global Burden Attributable to High Low-Density Lipoprotein-Cholesterol From 1990 to 2019.

Background: High low-density lipoprotein-cholesterol (LDL-C) is a public health issue contributing to ischemic heart disease (IHD) and stroke. Method: In this ecological study, we collected summary exposure values (SEVs), deaths, disability-adjusted life of years (DALYs), and Social Demographic Index (SDI) of high LDL-C from 1990 to 2019 using the query tool from the Global Burden of Disease (GBD) Collaborative Network. Outcomes include SEVs, deaths, and DALYs attributable to high LDL-C stratified by sex, age, region, SDI, countries, and territories. Estimated annual percentage changes (EAPCs) were applied to estimate annual trends of changes in these outcomes. We applied the weighted segmented regression with break-point estimation to detect the linear piecewise relationship between SDI and high LDL-C disease burden. Results: Globally, 3.00 million (95% uncertainty interval [UI], 2.35-3.76 million) people in 1990 and 4.40 million (95% UI, 3.30-5.65 million) people died from high LDL-C in 2019. The absolute annual burden from deaths and DALYs attributed to high LDL-C increased by 46% (95% UI, 35-56%) and 41% (95% UI, 31-50%) from 1990 to 2019. The age-standardized SEV, death, and DALY was decreased by 9% (95% UI, -11 to -8%), 37% (95% UI, -41-33%), and 32% (95% UI, -37 to -28%), respectively, during the study period. There was a negative association between SDI and high LDL-C-related age-standardized death and DALY rates when SDI surpassed 0.71 and 0.71, respectively. Conclusion: Although the overall age-standardized burden of high LDL-C is controlled in the past 30 years, it remains increasing in moderate SDI countries, and decreasing trends are disappearing in high SDI countries. New challenges require new actions stratified by countries with different SDI levels.

Safety of proprotein convertase subtilisin/kexin 9 inhibitors: a systematic review and meta-analysis.

OBJECTIVE: To determine the harms of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors in people who need lipid-lowering therapy. METHODS: This systematic review included randomised controlled trials that compared PCSK9 inhibitors with placebo, standard care or active lipid-lowering comparators in people who need lipid-lowering therapy with the follow-up duration of at least 24 weeks. We summarised the relative effects for potential harms from PCSK9 inhibitors using random-effect pairwise meta-analyses and assessed the certainty of evidence using GRADE (Grading of Recommendation Assessment, Development and Evaluation) for each outcome. RESULTS: We included 32 trials with 65 861 participants (with the median follow-up duration of 40 weeks, ranging from 24 to 146 weeks). The meta-analysis showed an incidence of injection-site reaction leading to discontinuation (absolute incidence of 15 events (95% CI 11 to 20) per 1000 persons in a 5-year time frame, high certainty evidence). PCSK9 inhibitors do not increase the risk of new-onset diabetes mellitus, neurocognitive events, cataracts or gastrointestinal haemorrhage with high certainty evidence. PCSK9 inhibitors probably do not increase the risks of myalgia or muscular pain leading to discontinuation or any adverse events leading to discontinuation with moderate evidence certainty. Given very limited evidence, PCSK9 inhibitors might not increase influenza-like symptoms leading to discontinuation (risk ratio 1.5; 95% CI 0.06 to 36.58). We did not identify credible subgroup analyses results, including shorter versus longer follow-up duration of trials. CONCLUSIONS: PCSK9 inhibitors slightly increase the risk of severe injection-site reaction but not cataracts, gastrointestinal haemorrhage, neurocognitive events, new-onset diabetes or severe myalgia or muscular pain.

Safety of ezetimibe in lipid-lowering treatment: systematic review and meta-analysis of randomised controlled trials and cohort studies.

Objective: To determine the harms of ezetimibe in people who need lipid-lowering treatment. Design: Systematic review and meta-analysis. Data sources: Randomised controlled trials and cohort studies. Eligibility criteria for selecting studies: Studies comparing ezetimibe with placebo, standard care, or other lipid-lowering agents in people who need lipid-lowering treatment with a follow-up duration of at least six months (or 24 weeks). The relative effects for potential harms of ezetimibe were pooled by use of random effect pairwise meta-analyses for randomised controlled trials and the evidence from observational studies was narratively summarised. The certainty of evidence was assessed using the Grading of Recommendation Assessment, Development, and Evaluation. Results: 48 randomised controlled trials with 28 444 participants (median follow-up 34 weeks, range 24-312 weeks) and four observational studies with 1667 participants (median follow-up 282 weeks, range 72-400 weeks) were included. The meta-analyses of randomised trials showed moderate to high certainty that ezetimibe was not associated with cancer (relative risk 1.01; 95% confidence interval 0.92 to 1.11), fractures (0.90; 0.74 to 1.10), discontinuation due to any adverse event (0.87; 0.74 to 1.03), gastrointestinal adverse events leading to discontinuation (1.34; 0.58 to 3.08), myalgia or muscular pain leading to discontinuation (0.82; 0.51 to 1.33), neurocognitive events (1.48; 0.58 to 3.81), or new-onset diabetes (0.88; 0.61 to 1.28). The narrative analysis of observational studies provided consistent findings. No credible subgroup effects were identified for the harm outcomes, including shorter versus longer follow-up duration of trials. Conclusions: Ezetimibe results in little to no difference in adverse events or other undesirable effects compared with placebo, usual care or other lipid-lowering agents. Review registration: PROSPERO CRD42020187437.

Effect of Anticoagulant Administration on the Mortality of Hospitalized Patients With COVID-19: An Updated Systematic Review and Meta-Analysis.

Background: Anticoagulation is generally used in hospitalized patients with coronavirus disease 2019 (COVID-19) as thromboprophylaxis. However, results from different studies comparing the effect of anticoagulation on the mortality of COVID-19 patients with non-anticoagulation are inconclusive. Methods: Our systematic review included observational trials if they studied anticoagulant therapy in hospitalized patients with COVID-19 for mortality or bleeding events. Dichotomous variables from individual studies were pooled by risk ratio (RR) and their 95% confidence interval (95% CI) using the random-effects model. Grading of Recommendations Assessment, Development and Evaluation was used to assess the quality of evidence. Results: A total of 11 observational studies enrolling 20,748 hospitalized COVID-19 patients overall were included. A pooled meta-analysis of these studies showed that anticoagulation therapy, compared with non-anticoagulation therapy, was associated with lower mortality risk (RR 0.70, 95% CI 0.52-0.93, p = 0.01). The evidence of benefit was stronger among critically ill COVID-19 patients in the intensive care units (RR 0.59, 95% CI 0.43-0.83, p = 0.002). Additionally, severe bleeding events were not associated with the administration of anticoagulants (RR 0.93, 95% CI 0.71-1.23, p = 0.63). Conclusion: Among patients with COVID-19 admitted to hospital, the administration of anticoagulants was associated with a decreased mortality without increasing the incidence of bleeding events.

A narrative review of exosomes in vascular calcification.

Vascular calcification (VC) is the abnormal deposition of calcium, phosphorus, and other minerals in the vessel wall and can be commonly observed in diabetes, chronic kidney disease, and chronic inflammatory disease. It is closely associated with mortality from cardiovascular events. Traditionally, calcification is considered as a degenerative disease associated with the aging process, while increasing evidence has shown that the occurrence and development of calcification is an active biological process, which is highly regulated by multiple factors. The molecular mechanisms of VC have not yet been fully elucidated. Exosomes, as important transporters of substance transport and intercellular communication, have been shown to participate in VC. The regulation of VC by exosomes involves a number of complex biological processes, which occur through a variety of interaction mechanisms. However, the specific role and mechanism of exosomes in the process of VC are still not fully understood and require further study. This review will briefly describe the roles of exosomes in the process of VC including in the promotion of extracellular mineral deposits, induction of phenotypic conversion of vascular smooth muscle cells (VSMCs), transport of microRNA between cells, and regulation on autophagy and oxidative stress, with the aim of providing novel ideas for the clinical diagnosis and treatment of VC.

Associations Between 25-Hydroxyvitamin D, Kidney Function, and Insulin Resistance Among Adults in the United States of America.

BACKGROUND: Although many molecular studies have tried to explore the relationship between vitamin D metabolism and kidney function, the association between 25-hydroxyvitamin D [25(OH)D] and kidney function is still controversial. Previous studies reported that low vitamin D status and decreased kidney function were associated with insulin resistance (IR). However, neither of them was confirmed by large population-based studies. This study evaluated the associations between 25(OH)D and kidney function and the associations between both of them and IR among adults in the United States of America (USA). METHODS: We analyzed 36,523 adults from the National Health and Nutrition Examination Survey (NHANES) (2001-2014). Kidney function was assessed by the estimated glomerular filtration rate (eGFR), and IR was assessed by homeostasis model assessment (HOMA-IR). All data were survey-weighted, and corresponding linear regression models were performed to examine the associations. RESULTS: The mean serum 25(OH)D levels were found to be increased in participants with decreased kidney function (eGFR <90 ml/min/1.73 m2), and each unit of decreased serum 25(OH)D concentrations predicted 0.453 ml/min/1.73 m2 (95% CI: 0.426 to 0.480, p < 0.0001) higher eGFR. In addition, each unit of decreased eGFR was associated with 0.007 higher HOMA-IR, while each unit of decreased 25(OH)D concentrations led to 0.025 higher HOMA-IR. CONCLUSIONS: Serum 25-hydroxyvitamin D concentrations were negatively associated with kidney function. IR appears in the early stage of kidney dysfunction, and both serum 25(OH)D concentrations and kidney function are negatively associated with IR. Clinicians should maintain appropriate serum 25(OH)D concentrations and doses of vitamin D supplements for different populations. The underlying mechanism of these associations still needs more research, especially the negative association between serum 25(OH)D concentrations and kidney function.

Predictors of successful discontinuation from renal replacement therapy during AKI: A meta-analysis.

The predictors of weaning time of renal replacement therapy (RRT) remain controversial for special patients suffering from acute kidney injury (AKI). The present work aims to perform a meta-analysis to evaluate proper predictors of RRT weaning in AKI patients. We systematically searched EMBASE, PubMed, and Cochrane Central Register of Controlled trials for literatures between 1984 and June 2019. Studies evaluating predictors of weaning success of RRT in patients of AKI were included. Random-effects model or fixed-effects model meta-analyses were performed to compute a standard mean difference (SMD). Newcastle-Ottawa Scale was employed to assess the risk of bias. We included 10 observational trials including 1453 patients. Twelve predictors including urine output, serum creatinine, serum urea, mean arterial pressure, central venous pressure, lactate, serum potassium, serum bicarbonate, pH value, SOFA score, urinary urea, and urinary creatinine were identified, showing urine output (p = 0.0000), serum creatinine (p = 0.008), serum potassium (p = 0.02), serum bicarbonate (p = 0.01), pH value (p = 0.03), urinary urea (p = 0.002), and urinary creatinine (p = 0.02) were significantly associated with weaning success. With the limited evidence, we speculate that urine output, serum creatinine, serum potassium, serum bicarbonate, pH value, urinary urea, and urinary creatinine might be associated with successful weaning.

Anticoagulant chitosan-kappa-carrageenan composite hydrogel sorbent for simultaneous endotoxin and bacteria cleansing in septic blood.

Here, we describe a green approach to fabricate genipin crosslinked chitosan-kappa-carrageenan composite hydrogels (C-K hydrogels) aiming at reducing endotoxin level and bacteria burden in septic blood synchronously. The chemical compositions and morphologies of the developed C-K hydrogels were characterized by Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy and scanning electron microscopy. The C-K hydrogels significantly inhibited adverse blood-material interactions such as hemolysis, complement activation, platelet activation and contact activation, and exhibited better anticoagulant properties than raw chitosan hydrogels. Most importantly, the optimized C2-K1 hydrogels were competent to eliminate 63.3 % of endotoxin in septic blood with a maximum adsorption capacity of 95.0 EU/g during a 3-h simulative hemoperfusion procedure. Bacteria cleansing experiments further demonstrated that the optimized C2-K1 hydrogels effectively decreased 46.0 % of E. coli and 68.7 % of S. aureus load, respectively. It is believed that the C-K hydrogels are promising hemoperfusion sorbents to treat severe septic patients.

Proprotein convertase subtilisin/kexin 9 inhibitors in reducing cardiovascular outcomes: a systematic review and meta-analysis.

BACKGROUND: To evaluate the effects of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors on major adverse cardiovascular events (MACE). METHODS: Our systematic review included randomised controlled trials if they studied PCSK9 inhibitors in patients for primary and/or secondary prevention of cardiovascular diseases or with hypercholesterolaemia/hyperlipidaemia. Dichotomous variables from individual studies were pooled by relative risks (RR) and their 95% CIs using the random-effect model. Risk difference (RD) in the 10-year frame was also estimated using the pooled RR and the estimated baseline risk using the control group. Grading of Recommendation Assessment, Development and Evaluation was used to assess the quality of evidence. RESULTS: We included 54 trials with 97 910 patients in the analysis. Compared with controls, PCSK9 inhibitors significantly reduced the risk of MACE by 16% (RR, 0.84; 95% CI 0.79 to 0.89; RD: 47 fewer per 1000 vs 286 as the baseline risk; 95% CI 32 to 59 fewer), non-fatal myocardial infarction (MI) by 17% (RR, 0.83; 95% CI 0.74 to 0.93; RD, 35 fewer per 1000 vs 207 as the baseline; 95% CI 13 to 53 fewer) and any stroke by 25% (RR, 0.75; 95% CI 0.65 to 0.85; RD, 16 fewer per 1000 vs 61 as the baseline; 95% CI 9 to 21 fewer) with moderate quality evidence. No significant differences were found between PCSK9 inhibitors and control groups in all-cause mortality, cardiovascular death, heart failure or unstable angina with low-quality evidence. CONCLUSIONS: This study demonstrated that PCSK9 inhibitors could significantly reduce the risk of MACE, non-fatal MI and stroke. TRIAL REGISTRATION: PROSPERO; CRD42017073904.

Exenatide in obese or overweight patients without diabetes: A systematic review and meta-analyses of randomized controlled trials.

BACKGROUND/OBJECTIVES: Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is increasingly used in obese or overweight patients with diabetes. However, its safety profile and effects on weight loss in non-diabetic obese or overweight population remain unclear. We aimed to evaluate efficacy and safety of exenatide in obese or overweight participants without diabetes. METHODS: We searched up to January 2016 in MEDLINE (Ovid SP), EMBASE (Ovid SP), Cochrane Central Register of Controlled Trials (CENTRAL), some Chinese databases and ClinicalTrials.gov for randomized controlled trials (RCTs) investigating exenatide in obese or overweight participants without diabetes. The primary outcomes included body weight and body mass index (BMI). We pooled data to calculate the mean differences (MDs) with their 95% confidence intervals (CIs). We assessed overall evidence quality of BMI reduction and weight loss according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Six randomized controlled trials involving 362 patients were included in the meta- analysis. The follow-up duration ranged from 12 to 24weeks. Compared with control group, a larger body weight loss (MD: -4.47kg; 95% CI: -6.67 to -2.27; P<0.0001), regardless of dosage and population, was achieved by the obese or overweight patients in exenatide group. Exenatide also elicited a greater reduction in BMI (MD: -0.86kg/m(2); 95% CI: -1.39 to -0.33; P=0.001) and waist circumferences (MD: -1.78cm; 95% CI: -3.13 to -0.44; P=0.009) compared with the control. No significant benefits were showed in exenatide group in terms of blood pressure and lipid profiles. Gastrointestinal adverse events were mostly common during the treatment of exenatide. CONCLUSIONS: Exenatide could significantly reduce body weight in obese or overweight participants without diabetes, and might be a safe alternative GLP-1 receptor agonist for weight control in such patients. Larger randomized trials with longer follow-up duration are required to confirm the effectiveness and safety of exenatide.