Cardiovascular Events In People Research Articles

Trends in Survival After First Myocardial Infarction in People With Diabetes.

The aim of this study was to investigate temporal trends in survival and subsequent cardiovascular events in a nationwide myocardial infarction population with and without diabetes. Between 2006 and 2020, we identified 2527 individuals with type 1 diabetes, 48 321 individuals with type 2 diabetes and 243 170 individuals without diabetes with first myocardial infarction in national health care registries. Outcomes were trends in all-cause death after 30 and 365 days, cardiovascular death and major adverse cardiovascular events (ie, nonfatal stroke, nonfatal myocardial infarction, cardiovascular death, and heart failure hospitalization). Pseudo-observations were used to estimate the mortality risk, with 95% CIs, using linear regression, adjusted for age and sex. Individuals with type 1 diabetes were younger (62±12.2 years) and more often women (43.6%) compared with individuals with type 2 diabetes (75±10.8 years; women, 38.1%), and individuals without diabetes (73±13.2 years; women, 38.4%). Early death decreased in people without diabetes from 23.1% to 17.5%, (annual change -0.48% [95% CI, -0.52% to -0.44%]) and in people with type 2 diabetes from 22.6% to 19.3% (annual change, -0.33% [95% CI, -0.43% to -0.24%]), with no such significant trend in people with type 1 diabetes from 23.8% to 21.7% (annual change, -0.18% [95% CI, -0.53% to 0.17%]). Similar trends were observed with regard to 1-year death, cardiovascular death, and major adverse cardiovascular events. During the past 15 years, the trend in survival and major adverse cardiovascular events in people with first myocardial infarction without diabetes and with type 2 diabetes have improved significantly. In contrast, a similar improvement was not seen in people with type 1 diabetes.

Risk of Cardiovascular Events in People with HIV (PWH) Treated with Integrase Strand-Transfer Inhibitors: The Debate Is Not Over; Results of the SCOLTA Study.

Cardiovascular disease (CVD) is common in people with HIV (PWH), and has great impact in terms of morbidity and mortality. Several intertwined mechanisms are believed to play a role in determining the increased risk of CVD, including the effect of certain antiretrovirals; among these, the role of integrase strand-transfer inhibitors (INSTIs) is yet to be fully elucidated. We conducted a multicenter, observational study comprising 4984 PWH evaluating the antiretroviral therapy (ART)-related nature of CVD in real life settings, both in naïve vs. treatment-experienced people. A comparison was conducted between INSTIs vs. either protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) considering demographic, baseline clinical characteristics, incidence of CVD in both 2-year and complete follow-up periods. Among 2357 PWH exposed to INSTIs, 24 people experienced CVD; the corresponding figure was 12 cases out of 2599 PWH exposed to other ART classes. At univariate and multivariate analysis, a tendency towards an increased risk of CVD was observed in the 2-year follow-up period in PWH exposed to INSTIs in the absence, however, of statistical significance. These findings leave open the hypothesis that INSTIs may play a role, albeit minimal, in determining an increased risk of CVD in PWH.

Screening for Subclinical Atherosclerosis and the Prediction of Cardiovascular Events in People with Type 1 Diabetes.

People with type 1 diabetes (T1D) have a high cardiovascular disease (CVD) risk, which remains the leading cause of death in this population. Despite the improved control of several classic risk factors, particularly better glycaemic control, cardiovascular morbidity and mortality continue to be significantly higher than in the general population. In routine clinical practice, estimating cardiovascular risk (CVR) in people with T1D using scales or equations is often imprecise because much of the evidence comes from pooled samples of people with type 2 diabetes (T2D) and T1D or from extrapolations of studies performed on people with T2D. Given that T1D onsets at a young age, prolonged exposure to the disease and its consequences (e.g., hyperglycaemia, changes in lipid metabolism or inflammation) have a detrimental impact on cardiovascular health. Therefore, it is critical to have tools that allow for the early identification of those individuals with a higher CVR and thus be able to make the most appropriate management decisions in each case. In this sense, atherosclerosis is the prelude to most cardiovascular events. People with diabetes present pathophysiological alterations that facilitate atherosclerosis development and that may imply a greater vulnerability of atheromatous plaques. Screening for subclinical atherosclerosis using various techniques, mainly imaging, has proven valuable in predicting cardiovascular events. Its use enables the reclassification of CVR and, therefore, an individualised adjustment of therapeutic management. However, the available evidence in people with T1D is scarce. This narrative review provides and updated overview of the main non-invasive tests for detecting atherosclerosis plaques and their association with CVD in people with T1D.

A randomized, placebo-controlled crossover trial to assess the influence of body weight on aspirin-triggered specialized pro-resolving mediators: Protocol for the DISCOVER Study.

Low-dose aspirin is ineffective for primary prevention of cardiovascular events in people with body weight greater than 70kg. While the prevalent explanation for this is reduced platelet cyclooxygenase-1 (COX-1) inhibition at higher body weights, supporting data are limited, thereby demanding further investigation of the reason(s) underlying this observation. We propose that aspirin-mediated cyclooxygenase-2 (COX-2) acetylation and the resulting synthesis of 15-epi-lipoxin A4, a specialized pro-resolving mediator, is suboptimal in higher weight individuals, which may contribute to the clinical trial findings. To test this hypothesis, we are conducting a double-blind, placebo-controlled, randomized, mechanistic crossover trial. Healthy men and women exhibiting a wide range of body weights take 81mg aspirin and 325mg aspirin for 3 weeks each, following 3-week placebo run-in and wash-out phases. Our target sample size is 90 subjects, with a minimum of 72 completing all visits estimated to be necessary to achieve power adequate to test our primary hypothesis. Our primary endpoint is the difference in change in plasma 15-epi-lipoxin A4 occurring with each dose of aspirin. Secondary endpoints include lipid mediator profiles, serum bioactive lipid profiles, and other endpoints involved in the resolution of vascular inflammation. Study enrollment began in November 2021 and is ongoing. The results of this study will improve our understanding of the mechanisms underlying aspirin's role(s) in the prevention of adverse cardiovascular outcomes. They may also lead to additional studies with the potential to inform dosing strategies for patients based on body weight.

Blood Monocyte Phenotype Is A Marker of Cardiovascular Risk in Type 2 Diabetes.

Diabetes is a major risk factor for atherosclerotic cardiovascular diseases with a 2-fold higher risk of cardiovascular events in people with diabetes compared with those without. Circulating monocytes are inflammatory effector cells involved in both type 2 diabetes (T2D) and atherogenesis. We investigated the relationship between circulating monocytes and cardiovascular risk progression in people with T2D, using phenotypic, transcriptomic, and metabolomic analyses. cardiovascular risk progression was estimated with coronary artery calcium score in a cohort of 672 people with T2D. Coronary artery calcium score was positively correlated with blood monocyte count and frequency of the classical monocyte subtype. Unsupervised k-means clustering based on monocyte subtype profiles revealed 3 main endotypes of people with T2D at varying risk of cardiovascular events. These observations were confirmed in a validation cohort of 279 T2D participants. The predictive association between monocyte count and major adverse cardiovascular events was validated through an independent prospective cohort of 757 patients with T2D. Integration of monocyte transcriptome analyses and plasma metabolomes showed a disruption of mitochondrial pathways (tricarboxylic acid cycle, oxidative phosphorylation pathway) that underlined a proatherogenic phenotype. In this study, we provide evidence that frequency and monocyte phenotypic profile are closely linked to cardiovascular risk in patients with T2D. The assessment of monocyte frequency and count is a valuable predictive marker for risk of cardiovascular events in patients with T2D. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04353869.

High dose semaglutide 2.4 mg (once weekly) shown to reduce the risks of cardiovascular events in people without diabetes

High dose semaglutide 2.4 mg (once weekly) shown to reduce the risks of cardiovascular events in people without diabetes

Effects of oral anticoagulation in people with atrial fibrillation after spontaneous intracranial haemorrhage (COCROACH): prospective, individual participant data meta-analysis of randomised trials

The safety and efficacy of oral anticoagulation for prevention of major adverse cardiovascular events in people with atrial fibrillation and spontaneous intracranial haemorrhage are uncertain. We planned to estimate the effects of starting versus avoiding oral anticoagulation in people with spontaneous intracranial haemorrhage and atrial fibrillation. In this prospective meta-analysis, we searched bibliographic databases and trial registries using the strategies of a Cochrane systematic review (CD012144) on June 23, 2023. We included clinical trials if they were registered, randomised, and included participants with spontaneous intracranial haemorrhage and atrial fibrillation who were assigned to either start long-term use of any oral anticoagulant agent or avoid oral anticoagulation (ie, placebo, open control, another antithrombotic agent, or another intervention for the prevention of major adverse cardiovascular events). We assessed eligible trials using the Cochrane Risk of Bias tool. We sought data for individual participants who had not opted out of data sharing from chief investigators of completed trials, pending completion of ongoing trials in 2028. The primary outcome was any stroke or cardiovascular death. We used individual participant data to construct a Cox regression model of the time to the first occurrence of outcome events during follow-up in the intention-to-treat dataset supplied by each trial, followed by meta-analysis using a fixed-effect inverse-variance model to generate a pooled estimate of the hazard ratio (HR) with 95% CI. This study is registered with PROSPERO, CRD42021246133. We identified four eligible trials; three were restricted to participants with atrial fibrillation and intracranial haemorrhage (SoSTART [NCT03153150], with 203 participants) or intracerebral haemorrhage (APACHE-AF [NCT02565693], with 101 participants, and NASPAF-ICH [NCT02998905], with 30 participants), and one included a subgroup of participants with previous intracranial haemorrhage (ELDERCARE-AF [NCT02801669], with 80 participants). After excluding two participants who opted out of data sharing, we included 412 participants (310 [75%] aged 75 years or older, 249 [60%] with CHA2DS2-VASc score ≤4, and 163 [40%] with CHA2DS2-VASc score >4). The intervention was a direct oral anticoagulant in 209 (99%) of 212 participants who were assigned to start oral anticoagulation, and the comparator was antiplatelet monotherapy in 67 (33%) of 200 participants assigned to avoid oral anticoagulation. The primary outcome of any stroke or cardiovascular death occurred in 29 (14%) of 212 participants who started oral anticoagulation versus 43 (22%) of 200 who avoided oral anticoagulation (pooled HR 0·68 [95% CI 0·42-1·10]; I2=0%). Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events (nine [4%] of 212 vs 38 [19%] of 200; pooled HR 0·27 [95% CI 0·13-0·56]; I2=0%). There was no significant increase in haemorrhagic major adverse cardiovascular events (15 [7%] of 212 vs nine [5%] of 200; pooled HR 1·80 [95% CI 0·77-4·21]; I2=0%), death from any cause (38 [18%] of 212 vs 29 [15%] of 200; 1·29 [0·78-2·11]; I2=50%), or death or dependence after 1 year (78 [53%] of 147 vs 74 [51%] of 145; pooled odds ratio 1·12 [95% CI 0·70-1·79]; I2=0%). For people with atrial fibrillation and intracranial haemorrhage, oral anticoagulation had uncertain effects on the risk of any stroke or cardiovascular death (both overall and in subgroups), haemorrhagic major adverse cardiovascular events, and functional outcome. Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events, which can inform clinical practice. These findings should encourage recruitment to, and completion of, ongoing trials. British Heart Foundation.

From Snoring to Soaring: Unveiling the Positive Effects of Continuous Positive Airway Pressure Ventilation on Cardiovascular Health in Patients With Obstructive Sleep Apnoea Through a Systematic Review.

Increased cardiovascular (CV) morbidity and death are linked to obstructive sleep apnoea (OSA). The primary method of treating OSA is continuous positive airway pressure (CPAP). CPAP has some debatable outcomes on CV events in people suffering from OSA. The current study investigates how CPAP affects CV outcomes. The goalis to evaluate CPAP's effectiveness in lowering CV outcomes in OSA patients.We used a computer to search the PubMed, PubMed Central Library, Science Direct, and Google Scholar databases for studies comparing the effects of CPAP and a control group on CV outcomes in OSA patients. These included randomised control trials (RCT), narrative reviews, systematic reviews, case-control studies, observational studies and meta-analyses. A total of 52,937 patients were included in the final analysis of six RCTs, four observational studies, 10 meta-analyses, one case-control study, two systematic reviews and one narrative review. The weighted mean follow-up lasted for a period of between three months and nine years. The risk of major cardiovascular adverse events (MACE) was the same for both the CPAP and control groups.According to subgroup analysis, patients with lower MACE adherence rates (four hours per night) were more likely to use CPAP. The risk of all-cause mortality, CV-related complications causing mortality, acute myocardial infarction acute stroke, or hospitalisations for angina was the same in the CPAP and control groups.The primary outcome was that in patients with therapy with CPAP in addition to usual care and usual care alone did not prevent CV events in patients with moderate-to-severe OSA and existing CV illness. Patients with OSA who utilise CPAP may not experience fewer CV events. Patients who use CPAP consistently (four hours per night) could benefit from improved CV results. Future research must assess how well-adherent patients with severe OSA and low CV event rates respond to CPAP therapy. In patients who use CPAP for more than four hours each night, CPAP therapy may minimise the risk of MACE and stroke. Additional randomised trials requiring adequate CPAP time adherence are needed to support this perception. Despite the fact that there is no evidence to support the claim that CPAP therapy improves CVoutcomes, bias difficulties, CPAP adherence problems, and the patient groups included in each RCT may have made it more difficult to generalise the findings to all patients. Future research is therefore needed to look at these relevant results.

Exploring SGLT-2 Inhibitors: Benefits beyond the Glucose-Lowering Effect—What Is New in 2023?

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors were once known as a class of glycemic-lowering agents to treat type 2 diabetes. As the evolving evidence from recent cardiorenal trials on these agents has shown—e.g., EMPA-REG OUTCOME, DECLARE-TIMI 58, CANVAS Program, DAPA-CKD—disclosing their benefits beyond glycemic management, SGLT-2 inhibitors have stimulated a shift in the management of T2DM and its comorbidities, specifically preventing cardiovascular events in people with ASCVD, preventing heart failure hospitalizations, and delaying the progression of chronic kidney disease. As a result, their usage beyond glycemic management has been included in clinical practice guidelines. Although SGLT-2 inhibitors have shown promising results in cardiorenal outcomes, patients have not had equal access to these agents, at least in the United States, suggesting a systemic issue of health inequity. This review article explores the mechanisms by which cardiorenal benefits are offered, the results of the landmark clinical trials for these agents, and their place in therapy.

Down the rabbit hole: reviewing the evidence for primary prevention of cardiovascular disease in people with obesity.

Obesity is a prevalent chronic disorder and a well-known risk factor for cardiovascular disease. However, the evidence of treating obesity for primary prevention of major cardiovascular events is still scarce and controversial. In this review, we provided a comprehensive description of the current evidence in treating obesity regarding cardiovascular protection. Bariatric surgery appears to be the most robust method to reduce events in people without established cardiovascular disease. High compliance to lifestyle interventions can further reduce cardiovascular risk. Concerning pharmacological therapies, a post hoc analysis from SUSTAIN-6 and a meta-analysis from STEP trials suggest that semaglutide, a GLP-1 receptor agonist, could reduce cardiovascular events in people without established cardiovascular disease. The first study addressed specifically a high-risk population with diabetes and, the second, low- or intermediary-risk individuals without diabetes. Tirzepatide, a novel dual GIP/GLP-1 agonist, although not yet tested in specific cardiovascular outcomes trials, could be an alternative since it induces loss in weight similar to the achieved by bariatric surgery. Therefore, extrapolated data in distinct baseline cardiovascular risk populations suggest that these two drugs could be used in primary prevention with the aim of preventing cardiovascular events, but the grade of this evidence is still low. Specifically designed studies are needed to address this specific topic.

971-P: Targeting Personalized Glycemic Response Led to Reduction in Glycemic Variability in Fitterfly CGM Diabetes Digital Therapeutics Program

Background and Aim: Glycemic variability (GV) has shown association with higher risk of diabetes-related complications and increased cardiovascular events in people with T2DM. Personalized glycemic response (PGR) refers to differences in postprandial glycemic response between two people after consumption of the same food. Understanding of PGR after meals can help in improving glycemic control. The study aims at assessing the real-world effectiveness of the PGR based Fitterfly Diabetes CGM program to reduce GV among people with T2DM. Methods: De-identified data of 220 participants (mean age: 48.8 ± 12.8 years, female: 35.9 % (79/220)), enrolled in the Fitterfly Diabetes CGM program was analyzed. CGM access was provided in the first 14 days of the program. In week-1, the users followed their usual lifestyle where blood sugar readings were correlated with meals and other lifestyle data to understand the PGR of each user. A modified lifestyle plan was introduced in week-2 and was followed till the end of the program. Mean blood glucose (mg/dL), TIR, TAR, TBR, glucose management indicator (GMI), and the percentage coefficient of variation for glucose (CV) were analyzed in week-1 and week-2. All data has been represented as median (IQR). Results: After 7 days, the median mean blood glucose and TAR significantly reduced by -4.3 (-14.8, 3.3) mg/dL (P<.001) and -2.5 (-11.6, 5.2) % (P<.001) from week-1 baseline of 130.4 (104.4, 169.7) mg/dl and 15.1 (2.8, 36.8) % respectively. The median TIR significantly increased by 1.7 (-2.8, 7.0) % from a baseline of 77.7 (57.2, 89.9) % (P=.001). The median GMI and CV was significantly reduced by -0.1 (-0.3, 0.1) % (P<.001) and -0.7 (-3.4, 1.8) % (P=.005) from baseline of 6.4 (5.8, 7.4) % and 26.9 (22.9, 31.9) % respectively. No significant change was observed in median TBR (P=.40). Conclusion: The study showed significant improvement in glycemic control and GV after 7 days of PGR-based guidance on the Fitterfly Diabetes CGM program. Disclosure R.Verma: Employee; Fitterfly Healthtech Pvt Ltd. S.Guntur: Employee; Fitterfly Health Tech Pvt. Ltd. A.K.Singal: Employee; Fitterfly Healthtech Pvt Ltd. M.A.Khader: Employee; Fitterfly Health Tech Pvt. Ltd. T.Lathia: None. S.R.Tanna: None. S.A.Patange: None. K.Samudra: None. R.M.Rohatgi: None. M.S.Chitale: None. R.M.Ranadive: Employee; Fitterfly Health Tech Pvt. Ltd. Funding Fitterfly Healthtech Pvt. Ltd.

468-P: Use of New Glucose-Lowering Drugs and the Risk of Major Adverse Cardiovascular Events in People with Type 2 Diabetes and Prior Stroke

Background: It remains uncertain whether the use of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and incretin-based drugs is associated with a reduced risk of major adverse cardiovascular events (MACE) compared with that of thiazolidinediones (TZDs) in people with type 2 diabetes and stroke. Objectives: To compare the effectiveness of SGLT2is, incretin-based drugs, and TZDs on MACE in people with type 2 diabetes and prior stroke. Methods: We did a population-based cohort study involving 117,355 individuals who underwent health checkups under the Korean National Health Insurance Service from 2014 to June 2021 and followed up until December 2021. The primary outcome was MACE, defined as a composite of myocardial infarction, ischemic stroke, and all-cause death. We used propensity score weighting for balancing baseline covariates between treatment groups. Weighted cox proportional regression analyses were used to estimate the association of treatments with MACE after adjusting confounders. Results: In a new-user cohort, the incidence rate of MACE was 547, 679, and 625 per 1,000 person-years in the SGLT2i, incretin-based drug, and TZD groups, respectively. Compared with the TZD group, the risk of MACE was significantly reduced in the SGLT2i group (adjusted hazard ratio [HR] 0.87; 95% CI 0.79-0.96) but increased in the incretin-based drug group (adjusted HR 1.11; 95% CI 1.03-1.19). No significant differences were observed in the risk of myocardial infarction and ischemic stroke between the groups. The risk of all-cause death was significantly increased in the incretin-based drug group (adjusted HR 1.14; 95% CI 1.03-1.25) compared with the TZD group. Conclusion: In this population-based study of people with type 2 diabetes and stroke, SGLT2is were associated with a reduced risk of MACE compared with incretin-based drugs and TZDs. Incretin-based drugs were associated with an increased risk of MACE compared with TZDs. Disclosure J.Bae: None. J.Choi: None. N.Kim: None. S.Kim: None.

Study design and baseline profile for adults with type 2 diabetes in the once-weekly subcutaneous SEmaglutide randomized PRAgmatic (SEPRA) trial

IntroductionOnce-weekly subcutaneous semaglutide, a glucagon-like peptide-1 analog, is approved in the USA as an adjunct to diet and exercise for adults with inadequately controlled type 2 diabetes (T2D) to improve...

Severe Infection and Risk of Cardiovascular Disease: A Multicohort Study.

The excess risk of cardiovascular disease associated with a wide array of infectious diseases is unknown. We quantified the short- and long-term risk of major cardiovascular events in people with severe infection and estimated the population-attributable fraction. We analyzed data from 331 683 UK Biobank participants without cardiovascular disease at baseline (2006-2010) and replicated our main findings in an independent population from 3 prospective cohort studies comprising 271 329 community-dwelling participants from Finland (baseline 1986-2005). Cardiovascular risk factors were measured at baseline. We diagnosed infectious diseases (the exposure) and incident major cardiovascular events after infections, defined as myocardial infarction, cardiac death, or fatal or nonfatal stroke (the outcome) from linkage of participants to hospital and death registers. We computed adjusted hazard ratios (HRs) and 95% CIs for infectious diseases as short- and long-term risk factors for incident major cardiovascular events. We also calculated population-attributable fractions for long-term risk. In the UK Biobank (mean follow-up, 11.6 years), 54 434 participants were hospitalized for an infection, and 11 649 had an incident major cardiovascular event at follow-up. Relative to participants with no record of infectious disease, those who were hospitalized experienced increased risk of major cardiovascular events, largely irrespective of the type of infection. This association was strongest during the first month after infection (HR, 7.87 [95% CI, 6.36-9.73]), but remained elevated during the entire follow-up (HR, 1.47 [95% CI, 1.40-1.54]). The findings were similar in the replication cohort (HR, 7.64 [95% CI, 5.82-10.03] during the first month; HR, 1.41 [95% CI, 1.34-1.48] during mean follow-up of 19.2 years). After controlling for traditional cardiovascular risk factors, the population-attributable fraction for severe infections and major cardiovascular events was 4.4% in the UK Biobank and 6.1% in the replication cohort. Infections severe enough to require hospital treatment were associated with increased risks for major cardiovascular disease events immediately after hospitalization. A small excess risk was also observed in the long-term, but residual confounding cannot be excluded.

Glucagon-Like Peptide-1 Receptor Agonists in Primary Care: Beyond Glycemic Control

Type 2 diabetes (T2D) is no longer considered solely a glucose-centric condition, but rather a chronic cardiometabolic disease that is linked to premature cardiovascular and renal complications and early death. Whereas previously, the level of glycemic control drove management decisions regarding treatment intensification, healthcare providers now have newer classes of agents that not only effectively lower glucose levels but also reduce the long-term risk of cardiovascular and renal complications. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) address several of the progressive multiorgan dysfunctions associated with T2D and a number of GLP-1RAs have been shown to reduce the risk of major adverse cardiovascular events in people with established cardiovascular disease or in those at high cardiovascular risk; GLP-1RAs (or a cardioprotective sodium-glucose cotransporter-2 inhibitor) should be considered in these high-risk patients regardless of their glycated hemoglobin goal attainment status. GLP-1RAs also facilitate substantial weight loss and there is some evidence that they may help to restore β-cell function and slow the decline of kidney function, although further studies are needed to confirm this.

Glucagon-Like Peptide 1 Therapy: From Discovery to Type 2 Diabetes and Beyond.

The therapeutic benefits of the incretin hormone, glucagon-like peptide 1 (GLP1), for people with type 2 diabetes and/or obesity, are now firmly established. The evidence-base arising from head-to-head comparative effectiveness studies in people with type 2 diabetes, as well as the recommendations by professional guidelines suggest that GLP1 receptor agonists should replace more traditional treatment options such as sulfonylureas and dipeptidyl-peptidase 4 (DPP4) inhibitors. Furthermore, their benefits in reducing cardiovascular events in people with type 2 diabetes beyond improvements in glycaemic control has led to numerous clinical trials seeking to translate this benefit beyond type 2 diabetes. Following early trial results their therapeutic benefit is currently being tested in other conditions including fatty liver disease, kidney disease, and Alzheimer's disease.

Epigenetics in Obesity and Diabetes Mellitus: New Insights

A long-term complication of obesity is the development of type 2 diabetes (T2D). Patients with T2D have been described as having epigenetic modifications. Epigenetics is the post-transcriptional modification of DNA or associated factors containing genetic information. These environmentally-influenced modifications, maintained during cell division, cause stable changes in gene expression. Epigenetic modifications of T2D are DNA methylation, acetylation, ubiquitylation, SUMOylation, and phosphorylation at the lysine residue at the amino terminus of histones, affecting DNA, histones, and non-coding RNA. DNA methylation has been shown in pancreatic islets, adipose tissue, skeletal muscle, and the liver. Furthermore, epigenetic changes have been observed in chronic complications of T2D, such as diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy. Recently, a new drug has been developed which acts on bromodomains and extraterminal (BET) domain proteins, which operate like epigenetic readers and communicate with chromatin to make DNA accessible for transcription by inhibiting them. This drug (apabetalone) is being studied to prevent major adverse cardiovascular events in people with T2D, low HDL cholesterol, chronic kidney failure, and recent coronary events. This review aims to describe the relationship between obesity, long-term complications such as T2D, and epigenetic modifications and their possible treatments.

PS-C08-7: TIME IN THERAPEUTIC RANGE IS NOT A RISK FACTOR FOR CARDIOVASCULAR DISEASE WHEN ADJUSTED FOR MEAN SYSTOLIC BLOOD PRESSURE

Background: Time in therapeutic range (TTR) has been suggested as a novel metric to assess blood pressure (BP) control, the quality of antihypertensive therapy, and the risk of cardiovascular events in people with hypertension. Methods: We used a validated electronic health record dataset, including all BP recordings in primary care in two Swedish counties from 1993 to 2011. People were eligible if they were 18 years or older, had a diagnosis of hypertension, no previous cardiovascular events, and at least five BP recordings during the first five years from the date of hypertension diagnosis. TTR was defined as the percentage of BP readings with a systolic value less than 140 mmHg. Participants were followed until death, migration or the 31st of December 2019. The risk of myocardial infarction and stroke was assessed using Cox proportional hazards model with TTR as independent variable, with and without mean systolic BP as a covariate. All analyses were adjusted for age, sex, diabetes, county, income and educational level. Results: 72 724 participants (56% female, mean age 62 years) were included in the analyses. The mean BP level during the first five years after diagnosis was 151/85 mmHg, with a median TTR of 17.7% (interquartile range 0–40%). During an average 7.7 years of follow-up, 6551 participants experienced a first-ever stroke and 5513 a first-ever myocardial infarction. In the unadjusted analyses, the risk of stroke decreased by 7% (HR 0.93, 95%CI 0.92–0.94) and the risk of myocardial infarction decreased by 6% (0.94, 0.93–0.95) for each 10 percentage points increase in TTR. When including mean systolic BP as a covariate, however, TTR was not associated with either stroke (0.99, 0.97–1.01) or myocardial infarction (1.00, 0.99–1.02). Conclusion: TTR for systolic BP is not an independent risk factor for stroke and myocardial infarction in clinical practice and does not add importantly to mean systolic BP as a measure of BP control.

PS-BPB06-1: GLOMERULAR HEMODYNAMIC CHANGES WITH SGLT2 INHIBITION IN TYPE 2 DIABETIC RATS USING IN VIVO IMAGING

Background and aim: Clinical trials have shown that sodium-glucose co-transporter 2 inhibitor (SGLT2i) not only reduce the risk of heart failure and cardiovascular events in people with type 2 diabetes, but also inhibit DKD progression. Improvement of glomerular hyperfiltration via tubuloglomerular feedback (TGF) is considered to be one of the possible pathways for renal protection with SGLT2i in DKD. However, the mechanisms responsible for kidney protection, especially in the setting of T2D, remain incompletely understood. In previous work, we established a method for measuring single nephron GFR (SNGFR) in mice using in vivo imaging and found that the adenosine/adenosine A1 receptor (A1aR) pathway is central for tubuloglomerular feedback (TGF) signaling and the pathogenesis of glomerular hyperfiltration in animal models of type 1 diabetes (Kidokoro K. et al. Circulation 2019). The mechanism of development of glomerular hyperfiltration, and improvement of glomerular hyperfiltration by SGLT2i may, however, be different in type 1 vs type 2 diabetes and related DKD. However, the detailed regulatory mechanism of GFR have not yet been elucidated in DKD related to T2D. Methods: Zucker lean (ZL) rats and Zucker diabetic fatty (ZDF) rats were used. In the first experiment, SNGFR and diameters of glomerular afferent/efferent arterioles were measured in both groups. Next, we examined the change of SNGFR and diameters of glomerular afferent/efferent arterioles, as well as urinary excretions of glucose and sodium in ZDF after a single-dose administration of SGLT2i (luseogliflozin; 10 mg/kg, gavage) for 120 minutes, which generated the following three groups: SGLT2i group, SGLT2i + adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine, 1 mg/kg) group, and insulin group. Results: SNGFR, afferent and efferent arteriole diameter were significantly increased in ZDF compared to ZL, with greater afferent vs. efferent dilatation. SGLT2i treatment resulted in correction of afferent arteriole vasodilation, with post-SGLT2i diameter that was comparable to baseline levels (p > 0.05). Post-SGLT2i SNGFR was also similar compared to baseline levels. Changes in efferent arteriole diameter were not significant. The inhibitory effect on hyperfiltration by SGLT2i was abolished by the concomitant use of an A1aR antagonist. In contrast, urinary sodium and urinary glucose in SGLT2 inhibitor group increased significantly regardless of adenosine A1 receptor antagonist use. In response to SGLT2i, urinary adenosine and PGE2 increased significantly (p > 0.05), while urine NOx did not change. Conclusion: Regulation of afferent arteriolar tone with SGLT2i is dependent on adenosine/ A1aR signaling an experimental model of T2D related hyperfiltration, regardless of ARB use.

The importance of methods for site performance evaluation in REPRIEVE, a longitudinal, global, multicenter trial

BackgroundREPRIEVE, the Randomized Trial to Prevent Vascular Events in HIV, is a multicenter, primary prevention trial evaluating whether a statin can prevent major cardiovascular events in people with HIV. REPRIEVE is conducted at >100 clinical research sites (CRSs) globally. Detailed, comprehensive, and novel methods for evaluating and communicating CRS performance are required to ensure trial integrity and data quality. In this analysis we describe a comprehensive multidimensional methodology for evaluating CRS performance. MethodsThe REPRIEVE Data Coordinating and Clinical Coordinating Centers developed a robust system for evaluation of and communication with CRSs, designed to identify potential issues and obstacles to performance, provide real-time technical support, and make recommendations for process improvements to facilitate efficient trial execution. We describe these systems and evaluate their impact on participant retention, data management, and specimen management from 2019 to 2022, corresponding to the period from end of recruitment to present. This evaluation was based on pre-defined metrics, regular reviews, and bidirectional communication. ResultsParticipant retention, data management, and specimen management all remained steady over the three-year period, although metrics varied by country of enrollment. Targeted messaging relating to certain performance metrics was effective. ConclusionSite performance is vital to ensure trial integrity and achievement of key trial goals. This analysis demonstrates that utilization of a comprehensive approach allows for a thorough evaluation of CRS performance, facilitates data and specimen management, and enhances participant retention. Our approach may serve as a guidepost for maximizing future large-scale clinical trials' operational success and scientific rigor.ClinicalTrials.gov Identifier: NCT02344290