Recurrent cardiovascular and limb events in 294,428 patients with coronary or peripheral artery disease or ischemic stroke on antiplatelet monotherapy: The RESRISK cohort study.

BACKGROUND AND AIMS: Utilising real-world data, we quantified the burden of cardiovascular risk factors and long-term residual risk of atherothrombotic events among routine care cohorts with coronary (CAD) or peripheral (PAD) artery disease or ischemic stroke (IS) on guideline-recommended antiplatelet monotherapy (APMT). METHODS: Retrospective cohort study using data (2010-2020) from the United Kingdom Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics, including adults with CAD, PAD or IS who were first prescribed APMT (CAD/IS: aspirin; PAD: clopidogrel). Primary outcomes (recurrent events): major adverse cardiovascular events (MACE) for CAD/PAD/IS cohorts, major adverse limb events (MALE) for PAD. RESULTS: 266,478 CAD, 13,162 PAD, and 14,788 IS patients were included (mean age: 71 years; women 37.7%-47.5 %). Risk factor burden was high and attainment of recommended goals was low. There were 73,691, 3,121 and 7,137 MACE among CAD, PAD and IS patients, respectively (median follow-up: 89.9, 42.4 and 75.9 months, respectively), and 4,767 MALE among PAD patients. MACE incidence rate per 1000 person-years was higher in IS (268.7; 95%CI 265.3-272.0) than CAD (92.9; 95%CI 92.5-93.4) or PAD cohorts (97.2; 95%CI 94.6-99.8). MALE incidence rate was 195.9 (95%CI 192.2-199.6) per 1000 person-years. IS patients presented a lower rate of hospitalisations and longer time-to-first hospitalisation, but once hospitalised, they had a longer length-of-stay. PAD patients had the highest hospitalisation rate. CONCLUSIONS: Among a contemporary cohort with cardiovascular disease on APMT, long-term residual atherothrombotic risk remains high despite being on APMT. Greater attention to risk factor control and use of appropriate evidence-based therapy is required to reduce residual risk among this very high-risk population.

Prescription of guideline-directed medical therapies in patients with diabetes and chronic kidney disease from the CURE-CKD Registry, 2019-2020.

AIM: Guideline-directed medical therapy (GDMT) is designed to improve clinical outcomes. The study aim was to assess GDMT prescribing rates and prescribing-persistence predictors in patients with diabetes and chronic kidney disease (CKD) from the Center for Kidney Disease Research, Education, and Hope Registry. MATERIALS AND METHODS: Data were obtained from adults ≥18 years old with diabetes and CKD between 1 January 2019 and 31 December 2020 (N = 39 158). Baseline and persistent (≥90 days) prescriptions for GDMT, including angiotensin converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB), sodium-glucose cotransporter-2 (SGLT2) inhibitor and glucagon-like peptide 1 (GLP-1) receptor agonist were assessed. RESULTS: The population age (mean ± SD) was 70 ± 14 years, and 49.6% (n = 19 415) were women. Baseline estimated glomerular filtration rate (2021 CKD-Epidemiology Collaboration creatinine equation) was 57.5 ± 23.0 ml/min/1.73 m2 and urine albumin/creatinine 57.5 mg/g (31.7-158.2; median, interquartile range). Baseline and ≥90-day persistent prescribing rates, respectively, were 70.7% and 40.4% for ACE inhibitor/ARB, 6.0% and 5.0% for SGLT2 inhibitors, and 6.8% and 6.3% for GLP-1 receptor agonist (all p < .001). Patients lacking primary commercial health insurance coverage were less likely to be prescribed an ACE inhibitor/ARB [odds ratio (OR) = 0.89; 95% confidence interval (CI) 0.84-0.95; p < .001], SGLT2 inhibitor (OR 0.72; 95% CI 0.64-0.81; p < .001) or GLP-1 receptor agonist (OR 0.89; 95% CI 0.80-0.98; p = .02). GDMT prescribing rates were lower at Providence than UCLA Health. CONCLUSIONS: Prescribing for GDMT was suboptimal and waned quickly in patients with diabetes and CKD. Type of primary health insurance coverage and health system were associated with GDMT prescribing.

The association between dual RAAS inhibition and risk of acute kidney injury and hyperkalemia in patients with diabetic kidney disease: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Dual renin-angiotensin-aldosterone system (RAAS) blockade involves dual therapy with a combination of angiotensin-converting enzyme inhibitors (ACEis), angiotensin-receptor blockers (ARBs), direct renin inhibitors (DRIs), or mineralocorticoid receptor antagonists (MRAs). It is hypothesized that dual RAAS blockade would result in a more complete inhibition of the RAAS cascade. However, large clinical trials on dual RAAS inhibition have shown increased risk of acute kidney injury (AKI) and hyperkalemia without additional benefit on mortality, cardiovascular events, or chronic kidney disease (CKD) progression compared to RAAS inhibitor monotherapy in patients with diabetic kidney disease (DKD). The development of newer, more selective non-steroidal MRAs as cardiorenal protective therapies has created a new opportunity for dual RAAS inhibition. We conducted a systematic review and meta-analysis of the risks of AKI and hyperkalemia with dual RAAS blockade in patients with DKD. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This is a systematic review and meta-analysis of the randomized controlled trials (RCT) published from 1 January 2006 to 30 May 2022. The study population included adult patients with DKD receiving dual RAAS blockade. A total of 31 RCTs and 33 048 patients were included in the systematic review. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using random effects. RESULTS: There were 208 AKI events in 2690 patients on ACEi + ARB versus 170 in 4264 patients with ACEi or ARB monotherapy (pooled RR 1.48, 95% CI: 1.23-1.39). There were 304 hyperkalemia events in 2818 patients on ACEi + ARB versus 208 in 4396 patients with ACEi or ARB monotherapy (pooled RR 1.97, 95% CI: 1.32-2.94). A non-steroidal MRA + ACEi or ARB showed no increase in the risk of AKI (pooled RR 0.97, 95% CI: 0.81-1.16) compared to ACEi or ARB monotherapy but had a 2-fold higher risk of hyperkalemia with 953 events in 7837 patients in dual therapy versus 454 events in 6895 patients in monotherapy (pooled RR 2.05, 95% CI: 1.84-2.28). A steroidal MRA + ACEi or ARB had a 5-fold higher risk of hyperkalemia with 28 events in 245 at risk in dual therapy versus five events in 248 at risk in monotherapy (pooled RR 5.42 95% CI: 2.15-13.67). CONCLUSION: Dual therapy with RAASi is associated with an increased risk of AKI and hyperkalemia compared to RAASi monotherapy. Conversely, dual therapy with RAAS inhibitors and non-steroidal MRAs have no additional risk of AKI but a similar risk of hyperkalemia, which is lower than dual therapy with RAAS inhibitors and steroidal MRAs.

Global Prevalence of Chronic Kidney Disease - A Systematic Review and Meta-Analysis.

Chronic kidney disease (CKD) is a global health burden with a high economic cost to health systems and is an independent risk factor for cardiovascular disease (CVD). All stages of CKD are associated with increased risks of cardiovascular morbidity, premature mortality, and/or decreased quality of life. CKD is usually asymptomatic until later stages and accurate prevalence data are lacking. Thus we sought to determine the prevalence of CKD globally, by stage, geographical location, gender and age. A systematic review and meta-analysis of observational studies estimating CKD prevalence in general populations was conducted through literature searches in 8 databases. We assessed pooled data using a random effects model. Of 5,842 potential articles, 100 studies of diverse quality were included, comprising 6,908,440 patients. Global mean(95%CI) CKD prevalence of 5 stages 13·4%(11·7-15·1%), and stages 3-5 was 10·6%(9·2-12·2%). Weighting by study quality did not affect prevalence estimates. CKD prevalence by stage was Stage-1 (eGFR>90+ACR>30): 3·5% (2·8-4·2%); Stage-2 (eGFR 60-89+ACR>30): 3·9% (2·7-5·3%); Stage-3 (eGFR 30-59): 7·6% (6·4-8·9%); Stage-4 = (eGFR 29-15): 0·4% (0·3-0·5%); and Stage-5 (eGFR<15): 0·1% (0·1-0·1%). CKD has a high global prevalence with a consistent estimated global CKD prevalence of between 11 to 13% with the majority stage 3. Future research should evaluate intervention strategies deliverable at scale to delay the progression of CKD and improve CVD outcomes.

Human SIRT1 regulates DNA binding and stability of the Mcm10 DNA replication factor via deacetylation.

The eukaryotic DNA replication initiation factor Mcm10 is essential for both replisome assembly and function. Human Mcm10 has two DNA-binding domains, the conserved internal domain (ID) and the C-terminal domain (CTD), which is specific to metazoans. SIRT1 is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that belongs to the sirtuin family. It is conserved from yeast to human and participates in cellular controls of metabolism, longevity, gene expression and genomic stability. Here we report that human Mcm10 is an acetylated protein regulated by SIRT1, which binds and deacetylates Mcm10 both in vivo and in vitro, and modulates Mcm10 stability and ability to bind DNA. Mcm10 and SIRT1 appear to act synergistically for DNA replication fork initiation. Furthermore, we show that the two DNA-binding domains of Mcm10 are modulated in distinct fashion by acetylation/deacetylation, suggesting an integrated regulation mechanism. Overall, our study highlights the importance of protein acetylation for DNA replication initiation and progression, and suggests that SIRT1 may mediate a crosstalk between cellular circuits controlling metabolism and DNA synthesis.

Human SIRT1 associates with mitotic chromatin and contributes to chromosomal condensation.

SIRT1 is a NAD-dependent deacetylase that participates in cellular controls of gene expression, metabolism, genomic stability and anti-aging. Here we report that SIRT1 levels rise in prometaphase leading to SIRT1 global association with mitotic chromatin until telophase. Moreover, SIRT1 contributes to chromosomal condensation by mediating chromosomal loading of histone H1 and the condensin I complex. Consistently, SIRT1 knockdown led to improper condensation and overall aberrant mitosis. Our data highlight new role for SIRT1 in maintenance of chromosome stability in mitosis and suggests how diminished SIRT1 activity during aging and tumorigenesis may lead to aneuploidy and genomic instability.