A Comparison of Sodium-Glucose Co-Transporter 2 Inhibitor Kidney Outcome Trial Participants with a Real-World Chronic Kidney Disease Primary Care Population.

BACKGROUND/HYPOTHESIS: Observational studies suggest sodium-glucose co-transporter-2 (SGLT2) inhibitor kidney outcome trials are not representative of the broader population of people with chronic kidney disease (CKD). However, there are limited data on the generalisability to those without co-existing type 2 diabetes (T2D), and the representativeness of the EMPA-KIDNEY trial has not been adequately explored. We hypothesised that SGLT2 inhibitor kidney outcome trials are more representative of people with co-existing T2D than those without, and that EMPA-KIDNEY is more representative than previous trials. METHODS: A cross-sectional analysis of adults with CKD in English primary care was conducted using the Oxford-Royal College of General Practitioners Clinical Information Digital Hub. The proportions that met the eligibility criteria of SGLT2 inhibitor kidney outcome trials were determined, and their characteristics described. Logistic regression analyses were performed to identify factors associated with trial eligibility. RESULTS: Of 6,670,829 adults, 516,491 (7.7%) with CKD were identified. In the real-world CKD population, 0.9%, 2.2%, and 8.0% met the CREDENCE, DAPA-CKD, and EMPA-KIDNEY eligibility criteria, respectively. All trials were more representative of people with co-existing T2D than those without T2D. Trial participants were 9-14 years younger than the real-world CKD population, and had more advanced CKD, including higher levels of albuminuria. A higher proportion of the CREDENCE (100%), DAPA-CKD (67.6%) and EMPA-KIDNEY (44.5%) trial participants had T2D compared to the real-world CKD population (32.8%). Renin-angiotensin system inhibitors were prescribed in almost all trial participants, compared to less than half of the real-world CKD population. Females were under-represented and less likely to be eligible for the trials. CONCLUSION: SGLT2 inhibitor kidney outcome trials represent a sub-group of people with CKD at high risk of adverse kidney events. Out study highlights the importance of complementing trials with real-world studies, exploring the effectiveness of SGLT2 inhibitors in the broader population of people with CKD.

Sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: Are clinical trial benefits for heart failure reflected in real-world clinical practice? A systematic review and meta-analysis of observational studies.

AIM: To determine the absolute risk reduction (ARR) of heart failure events in people treated with sodium-glucose co-transporter-2 (SGLT2) inhibitors. MATERIALS AND METHODS: We searched PubMed, EMBASE, CINAHL and ISI Web of Science for observational studies published to 9 May 2022 that explored the association between SGLT2 inhibitors and any indication for heart failure (including new diagnosis or hospitalization for heart failure) in type 2 diabetes. Identified studies were independently screened by two reviewers and assessed for bias using the Newcastle-Ottawa scale. Eligible studies with comparable outcome data were pooled for meta-analysis using random-effects models, reporting hazard ratios (HRs) with 95% confidence intervals (CIs). The ARR per 100 person-years was determined overall, and in subgroups with and without baseline cardiovascular disease (CVD). RESULTS: From 43 eligible studies, with a total of 4 818 242 participants from 17 countries, 21 were included for meta-analysis. SGLT2 inhibitors were associated with a reduced risk of hospitalization for heart failure (HR 0.65, 95% CI 0.59-0.72) overall and both in those with CVD (HR 0.78, 95% CI 0.68-0.89) and without CVD (HR 0.53, 95% CI 0.39-0.71). Risk reduction for hospitalization for heart failure in people with a history of CVD (ARR 1.17, 95% CI 0.78-1.55) was significantly greater than for those without CVD (ARR 0.39, 95% CI 0.32-0.47). The number-needed-to-treat to prevent one event of hospitalization for heart failure was 86 (95% CI 65-128) person-years of treatment for the CVD group and 256 (95% CI 215-316) person-years for those without CVD. CONCLUSIONS: Real-world SGLT2 inhibitor use supports randomized trial data for the size effect of reduced hospitalization for heart failure in type 2 diabetes, although with a much lower ARR in people without CVD.

Sodium-glucose cotransporter-2 inhibitors and kidney outcomes in real-world type 2 diabetes populations: A systematic review and meta-analysis of observational studies.

AIM: To conduct a systematic review of observational studies to explore the real-world kidney benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors in a large and diverse population of adults with type 2 diabetes (T2D). MATERIALS AND METHODS: We searched MEDLINE, EMBASE and Web of Science for observational studies that investigated kidney disease progression in adults with T2D treated with SGLT2 inhibitors compared to other glucose-lowering therapies. Studies published from database inception to July 2022 were independently reviewed by two authors and evaluated using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool. A random-effects meta-analysis was performed on studies with comparable outcome data, reported as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: We identified 34 studies performed across 15 countries with a total population of 1 494 373 for inclusion. In the meta-analysis of 20 studies, SGLT2 inhibitors were associated with a 46% lower risk of kidney failure events compared with other glucose-lowering drugs (HR 0.54, 95% CI 0.47-0.63). This finding was consistent across multiple sensitivity analyses and was independent of baseline estimated glomerular filtration rate (eGFR) or albuminuria status. SGLT2 inhibitors were associated with a lower risk of kidney failure when compared with dipeptidyl peptidase-4 inhibitors and a combination of other glucose-lowering drug classes (HR 0.50, 95% CI 0.38-0.67 and HR 0.51, 95% CI 0.44-0.59, respectively). However, when compared to glucagon-like peptide 1 receptor agonists there was no statistically significant difference in the risk of kidney failure (HR 0.93, 95% CI 0.80-1.09). CONCLUSIONS: The reno-protective benefits of SGLT2 inhibitors apply to a broad population of adults with T2D treated in routine clinical practice, including those at lower risk of kidney events with normal eGFR and without albuminuria. These findings support the early use of SGLT2 inhibitors in T2D for preservation of kidney health.

Diabetes foot complications and standardized mortality rate in type 2 diabetes.

AIM: To quantify the impact of foot complications on mortality outcomes in people with type 2 diabetes (T2D), and how routinely measured factors might modulate that risk. MATERIALS AND METHODS: Data for individuals with T2D for 2010-2020, from the Salford Integrated Care Record (Salford, UK), were extracted for laboratory and clinical data, and deaths. Annual expected deaths were taken from Office of National Statistics mortality data. An index of multiple deprivation (IMD) adjusted the standardized mortality ratio (SMR_IMD). Life years lost per death (LYLD) was estimated from the difference between expected and actual deaths. RESULTS: A total of 11 806 T2D patients were included, with 5583 new diagnoses and 3921 deaths during 2010-2020. The number of expected deaths was 2135; after IMD adjustment, there were 2595 expected deaths. Therefore, excess deaths numbered 1326 (SMR_IMD 1.51). No foot complications were evident in n = 9857. This group had an SMR_IMD of 1.13 and 2.74 LYLD. In total, 2979 patients had any foot complication recorded. In this group, the SMD_IMR was 2.29; of these, 2555 (75%) had only one foot complication. Patients with a foot complication showed little difference in percentage HbA1c more than 58 mmol/mol. In multivariate analysis, for those with a foot complication and an albumin-to-creatinine ratio of more than 3 mg/mmol, the odds ratio (OR) for death was 1.93, and for an estimated glomerular filtration rate of less than 60 mL/min/1.73m2 , the OR for death was 1.92. CONCLUSIONS: Patients with T2D but without a foot complication have an SMR_IMD that is only slightly higher than that of the general population. Those diagnosed with a foot complication have a mortality risk that is double that of those without T2D.

Mortality from angiotensin-converting enzyme-inhibitors and angiotensin receptor blockers in people infected with COVID-19: a cohort study of 3.7 million people.

BACKGROUND: Concerns have been raised that angiotensin-converting enzyme-inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) might facilitate transmission of severe acute respiratory syndrome coronavirus 2 leading to more severe coronavirus disease (COVID-19) disease and an increased risk of mortality. We aimed to investigate the association between ACE-I/ARB treatment and risk of death amongst people with COVID-19 in the first 6 months of the pandemic. METHODS: We identified a cohort of adults diagnosed with either confirmed or probable COVID-19 (from 1 January to 21 June 2020) using computerized medical records from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) primary care database. This comprised 465 general practices in England, United Kingdom with a nationally representative population of 3.7 million people. We constructed mixed-effects logistic regression models to quantify the association between ACE-I/ARBs and all-cause mortality among people with COVID-19, adjusted for sociodemographic factors, comorbidities, concurrent medication, smoking status, practice clustering, and household number. RESULTS: There were 9,586 COVID-19 cases in the sample and 1,463 (15.3%) died during the study period between 1 January 2020 and 21 June 2020. In adjusted analysis ACE-I and ARBs were not associated with all-cause mortality (adjusted odds ratio [OR] 1.02, 95% confidence interval [CI] 0.85-1.21 and OR 0.84, 95% CI 0.67-1.07, respectively). CONCLUSION: Use of ACE-I/ARB, which are commonly used drugs, did not alter the odds of all-cause mortality amongst people diagnosed with COVID-19. Our findings should inform patient and prescriber decisions concerning continued use of these medications during the pandemic.

Mortality in COVID-19 among women on hormone replacement therapy: a retrospective cohort study.

BACKGROUND: Limited recent observational data have suggested that there may be a protective effect of oestrogen on the severity of COVID-19 disease. Our aim was to investigate the association between hormone replacement therapy (HRT) or combined oral contraceptive pill (COCP) use and the likelihood of death in women with COVID-19. METHODS: We undertook a retrospective cohort study using routinely collected computerized medical records from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) primary care database. We identified a cohort of 1,863,478 women over 18 years of age from 465 general practices in England. Mixed-effects logistic regression models were used to quantify the association between HRT or COCP use and all-cause mortality among women diagnosed with confirmed or suspected COVID-19 in unadjusted and adjusted models. RESULTS: There were 5,451 COVID-19 cases within the cohort. HRT was associated with a reduction in all-cause mortality in COVID-19 (adjusted OR 0.22, 95% CI 0.05 to 0.94). There were no reported events for all-cause mortality in women prescribed COCPs. This prevented further examination of the impact of COCP. CONCLUSIONS: We found that HRT prescription within 6 months of a recorded diagnosis of COVID-19 infection was associated with a reduction in all-cause mortality. Further work is needed in larger cohorts to examine the association of COCP in COVID-19, and to further investigate the hypothesis that oestrogens may contribute a protective effect against COVID-19 severity.

Prescribing sodium-glucose co-transporter-2 inhibitors for type 2 diabetes in primary care: influence of renal function and heart failure diagnosis.

BACKGROUND: Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are licenced for initiation for glucose lowering in people with type 2 diabetes (T2DM) with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2). However, recent trial data have shown that these medications have renal and cardio-protective effects, even for impaired kidney function. The extent to which trial evidence and updated guidelines have influenced real-world prescribing of SGLT-2is is not known, particularly with co-administration of diuretics. METHODS: We performed a cross-sectional analysis of people with T2DM registered with practices in the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database on the 31st July 2019. We calculated the percentage of people prescribed SGLT-2is according to eGFR categories (< 45, 45-59, and ≥ 60 mL/min/1.73m2), with a heart failure diagnosis and stratified by body mass index categories (underweight, normal weight, overweight, obese), and with concomitant prescription of a diuretic. Multilevel logistic regression analysis was performed to determine whether heart failure diagnosis and renal function were associated with SGLT-2i prescribing. RESULTS: From a population of 242,624 people with T2DM across 419 practices, 11.0% (n = 26,700) had been prescribed SGLT-2is. The majority of people initiated SGLT-2is had an eGFR ≥ 60 mL/min/1.73m2 (93.2%), and 4.3% had a heart failure diagnosis. 9,226 (3.8%) people were prescribed SGLT-2is as an add-on to their diuretic prescription. People in the highest eGFR category (≥ 60 mL/min/1.73m2) were more likely to be prescribed SGLT-2is than those in eGFR lower categories. Overweight (OR 2.05, 95% CI 1.841-2.274) and obese people (OR 3.84, 95% CI 3.472-4.250) were also more likely to be prescribed these medications, whilst use of diuretics (OR 0.74, 95% CI 0.682-0.804) and heart failure (OR 0.81, 95% CI 0.653-0.998) were associated with lower odds of being prescribed SGLT-2is. CONCLUSIONS: Prescribing patterns of SGLT-2is for glucose lowering in T2DM in primary care generally concur with licenced indications according to recommended renal thresholds. A small percentage of people with heart failure were prescribed SGLT-2is for T2DM. An updated analysis is merited should UK National Institute for Health Care and Excellence prescribing guidelines for T2DM be revised to incorporate new data on the benefits for those with reduced renal function or with heart failure.

Effect of type 1 diabetes and type 2 diabetes on the risk of venous thromboembolism.

AIMS: Whether diabetes increases venous thromboembolism (VTE) is unclear. Any greater risk may relate to insulin resistance, but many studies did not differentiate between type 1 diabetes and type 2 diabetes for VTE risk. METHODS: Retrospective cohort study of the Royal College of General Practitioners Research and Surveillance Centre, comprising over 530 primary care practices. We determined whether type 1 diabetes and/or type 2 diabetes are independent risk factors for VTE. The index date was 1 January 2009, individuals were followed to 31 December 2018, or censoring. Cox proportional hazard regression analysis was used to investigate the risk of VTE in people with type 1 diabetes and type 2 diabetes relative to no diabetes. The primary outcome was occurrence of VTE. The model was adjusted for potential confounders for VTE. RESULTS: There were 7086 people with type 1 diabetes and 95,566 with type 2 diabetes, diagnosed before 1 January 2009. The non-diabetes group consisted of 1,407,699 people. In the unadjusted analysis, there was no increased risk of VTE with type 1 diabetes (HR 1.00, 95% CI 0.76-1.33) but there was for type 2 diabetes (HR 2.70, 95% CI 2.57-2.84). In the fully adjusted model, VTE risk was increased in type 1 diabetes (HR 1.46, 95% CI 1.11-1.92), but not with type 2 diabetes (HR 1.06, 95% CI 0.98-1.14). CONCLUSIONS: Type 1 diabetes was associated with a greater risk for VTE while type 2 diabetes was not. Further work is needed to determine the reason(s) for this.

Diabetes, obesity and COVID-19: A complex interplay.

With the accumulation of observational data showing an association of metabolic co-morbidities with adverse outcomes from COVID-19, there is a need to disentangle the contributions of pre-existing macro- and microvascular disease, obesity and glycaemia. This article outlines the complex mechanistic and clinical interplay between diabetes and COVID-19, the clinical and research questions which arise from this relationship, and the types of studies needed to answer those questions. The authors are clinicians and academics working in diabetes and obesity medicine, but the article is pitched to an audience of generalists with clinical experience of or interest in the management of COVID-19.

Real-world prevalence of the inclusion criteria for the LEADER trial: Data from a national general practice network.

AIMS: To explore the prevalence and describe the clinical characteristics of people with type 2 diabetes with a similar cardiovascular (CV) profile to that of the LEADER trial participants in a primary care setting in England. MATERIALS AND METHODS: In this cross-sectional analysis, using the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network database, we identified people with type 2 diabetes meeting the LEADER inclusion criteria. We identified people's CV risk factors using computerized medical records. Additionally, we assessed the prescription pattern of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in this cohort. RESULTS: Of 1 275 461 adults, we identified 84 394 with type 2 diabetes, of whom 14 000 (16.6%) met the LEADER inclusion criteria for established or high-risk CV disease (RCGP RSC-CVD group). The LEADER cohort was younger than the RCGP RSC-CVD group (64.2 vs 73.2 years), had higher mean glycated haemoglobin (71.6 vs 67.1 mmol/mol) and blood pressure (BP) values (systolic BP: 135.9 vs 132.9 mmHg; diastolic BP: 77.2 vs 72.7 mmHg), and a higher mean body mass index (32.5 vs 30.9 kg/m2 ). In the RCGP RSC-CVD group, only 1215 people (8.7%) had ever been prescribed a GLP-1RA and 760 (5.4%) had ever received liraglutide. CONCLUSIONS: In a cohort of English general practice patients, one in six people with type 2 diabetes met the LEADER inclusion criteria, and less than one in 10 of these received liraglutide, a drug which has demonstrated CV benefits amongst others. There is scope to improve the outlook in people with type 2 diabetes and high CV risk through evidence-based use of specific GLP-1RAs.

Intensification to injectable therapy in type 2 diabetes: mixed methods study (protocol).

BACKGROUND: In the UK, type 2 diabetes mellitus (T2D) is largely managed in primary care. Delay in the intensification to injectable therapy, a form of clinical inertia, is associated with worse glycaemic control. UK general practice is highly computerised, with care being recorded on computerised medical record systems; this allows for quantitative analysis of clinical care but not of the underpinning decision-making process. The aim of this study is to investigate perceptions of patients and clinicians in primary care on the initiation of injectable therapies in T2D, and the context within which those decisions are made. METHODS: This is a mixed methods study, taking a "realist evaluation" approach. The qualitative components comprise focus groups, interviews, and video recordings of simulated surgeries; the quantitative analysis: an overview of participating practices, elements of the video recording, and an online survey. We will recruit primary care clinicians (general practitioners and nurses) and patients from a representative sample of practices within the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network. Participants will be patients with T2D, and primary care clinicians. Focus groups and semi-structured interviews will be recorded, transcribed verbatim and analysed using Framework Analysis. The simulated surgeries will include cases that might be escalated to injectable therapy. The consultation will be reviewed using the Calgary-Cambridge model to assess communication and determination of adherence to national prescribing guidelines. We will conduct multi-channel video recording including screen capture, clinician and patient facial expressions, wide angle view of the consultation, and the computerised medical record screen. This allows annotation and qualitative analysis of the video recordings, and statistical analyses for the quantitative data. We will also conduct an online survey of primary care clinicians' attitudes to, and perceptions of, initiation of injectable therapies, which will be analysed using summary statistics. DISCUSSION: Results aim to provide a detailed insight into the dynamic two-way decision-making process underpinning use of injectable therapy for T2D. The study will provide insights into clinical practice and enable the development of training, interventions and guidelines that may facilitate, where appropriate, the intensification to injectable therapy.

Implementation of chronic kidney disease guidelines for sodium-glucose co-transporter-2 inhibitor use in primary care in the UK: a cross-sectional study.

Background: The cardiovascular and kidney benefits of sodium-glucose co-transporter-2 (SGLT2) inhibitors in people with chronic kidney disease (CKD) are well established. The implementation of updated SGLT2 inhibitor guidelines and prescribing in the real-world CKD population remains largely unknown. Methods: A cross-sectional study of adults with CKD registered with UK primary care practices in the Oxford-Royal College of General Practitioners Research and Surveillance Centre network on the 31st December 2022 was undertaken. Pseudonymised data from electronic health records held securely within the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub (ORCHID) were extracted. An update to a previously described ontological approach was used to identify the study population, using a combination of Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) indicating a diagnosis of CKD and laboratory confirmed CKD based on Kidney Disease: Improving Global Outcomes (KDIGO) diagnostic criteria. We examined the extent to which SGLT2 inhibitor guidelines apply to and are then implemented in adults with CKD. A logistic regression model was used to identify factors associated with SGLT2 inhibitor prescribing, reported as odds ratios (ORs) with 95% confidence intervals (CI). The four guidelines under investigation were the United Kingdom Kidney Association (UKKA) Clinical Practice Guideline SGLT2 Inhibition in Adults with Kidney Disease (October 2021), American Diabetes Association (ADA) and KDIGO Consensus Report on Diabetes Management in CKD (October 2022), National Institute for Health and Care Excellence (NICE) Guideline Type 2 Diabetes in Adults: Management (June 2022), and NICE Technology Appraisal Dapagliflozin for Treating CKD (March 2022). Findings: Of 6,670,829 adults, we identified 516,491 (7.7%) with CKD, including 32.8% (n = 169,443) who had co-existing type 2 diabetes (T2D). 26.8% (n = 138,183) of the overall CKD population had a guideline directed indication for SGLT2 inhibitor treatment. A higher proportion of people with CKD and co-existing T2D were indicated for treatment, compared to those without T2D (62.8% [n = 106,468] vs. 9.1% [n = 31,715]). SGLT2 inhibitors were prescribed to 17.0% (n = 23,466) of those with an indication for treatment, and prescriptions were predominantly in those with co-existing T2D; 22.0% (n = 23,464) in those with T2D, and <0.1% (n = 2) in those without T2D. In adjusted multivariable analysis of people with CKD and T2D, females (OR 0.69, 95% CI 0.67-0.72, p <0.0001), individuals of Black ethnicity (OR 0.84, 95% CI 0.77-0.91, p <0.0001) and those of lower socio-economic status (OR 0.72, 95% CI 0.68-0.76, p <0.0001) were less likely to be prescribed an SGLT2 inhibitor. Those with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 had a lower likelihood of receiving an SGLT2 inhibitor, compared to those with an eGFR ≥60 mL/min/1.73 m2 (eGFR 45-60 mL/min/1.73 m2 OR 0.65, 95% CI 0.62-0.68, p <0.0001, eGFR 30-45 mL/min/1.73 m2 OR 0.73, 95% CI 0.69-0.78, p <0.0001, eGFR 15-30 mL/min/1.73 m2 OR 0.52, 95% CI 0.46-0.60, p <0.0001, eGFR <15 mL/min/1.73 m2 OR 0.03, 95% CI 0.00-0.23, p = 0.0037, respectively). Those with albuminuria (urine albumin-to-creatinine ratio 3-30 mg/mmol) were less likely to be prescribed an SGLT2 inhibitor, compared to those without albuminuria (OR 0.78, 95% CI 0.75-0.82, p <0.0001). Interpretation: SGLT2 inhibitor guidelines in CKD have not yet been successfully implemented into clinical practice, most notably in those without co-existing T2D. Individuals at higher risk of adverse outcomes are paradoxically less likely to receive SGLT2 inhibitor treatment. The timeframe between the publication of guidelines and data extraction may have been too short to observe changes in clinical practice. Enhanced efforts to embed SGLT2 inhibitors equitably into routine care for people with CKD are urgently needed, particularly in those at highest risk of adverse outcomes and in the absence of T2D. Funding: None.

AZD1222 effectiveness against severe COVID-19 in individuals with comorbidity or frailty: The RAVEN cohort study.

OBJECTIVES: Despite being prioritized during initial COVID-19 vaccine rollout, vulnerable individuals at high risk of severe COVID-19 (hospitalization, intensive care unit admission, or death) remain underrepresented in vaccine effectiveness (VE) studies. The RAVEN cohort study (NCT05047822) assessed AZD1222 (ChAdOx1 nCov-19) two-dose primary series VE in vulnerable populations. METHODS: Using the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub, linked to secondary care, death registration, and COVID-19 datasets in England, COVID-19 outcomes in 2021 were compared in vaccinated and unvaccinated individuals matched on age, sex, region, and multimorbidity. RESULTS: Over 4.5 million AZD1222 recipients were matched (mean follow-up ∼5 months); 68% were ≥50 years, 57% had high multimorbidity. Overall, high VE against severe COVID-19 was demonstrated, with lower VE observed in vulnerable populations. VE against hospitalization was higher in the lowest multimorbidity quartile (91.1%; 95% CI: 90.1, 92.0) than the highest quartile (80.4%; 79.7, 81.1), and among individuals ≥65 years, higher in the 'fit' (86.2%; 84.5, 87.6) than the frailest (71.8%; 69.3, 74.2). VE against hospitalization was lowest in immunosuppressed individuals (64.6%; 60.7, 68.1). CONCLUSIONS: Based on integrated and comprehensive UK health data, overall population-level VE with AZD1222 was high. VEs were notably lower in vulnerable groups, particularly the immunosuppressed.

Trends in direct oral anticoagulant (DOAC) prescribing in English primary care (2014-2019).

BACKGROUND: In England, most prescribing of direct-acting oral anticoagulants for atrial fibrillation (AF) is in primary care. However, there remain gaps in our understanding of dosage and disparities in use. We aimed to describe trends in direct oral anticoagulant (DOAC) prescribing, including dose reduction in people with renal impairment and other criteria, and adherence. METHODS: Using English primary care sentinel network data from 2014 to 2019, we assessed appropriate DOAC dose adjustment with creatinine clearance (CrCl). Our primary care sentinel cohort was a subset of 722 general practices, with 6.46 million currently registered patients at the time of this study. RESULTS: Of 6 464 129 people in the cohort, 2.3% were aged ≥18 years with a diagnosis of AF, and 30.8% of these were prescribed vitamin K antagonist and 69.1% DOACs. Appropriate DOAC prescribing following CrCl measures improved between 2014 and 2019; dabigatran from 21.3% (95% CI 15.1% to 28.8%) to 48.7% (95% CI 45.0% to 52.4%); rivaroxaban from 22.1% (95% CI 16.7% to 28.4%) to 49.9% (95% CI 48.5% to 53.3%); edoxaban from 10.0% (95% CI 0.3% to 44.5%) in 2016 to 57.6% (95% CI 54.5% to 60.7%) in 2019; apixaban from 30.8% (95% CI 9.1% to 61.4%) in 2015 to 60.5% (95% CI 57.8% to 63.2%) in 2019.Adherence was highest for factor Xa inhibitors, increasing from 50.1% (95% CI 47.7% to 52.4%) in 2014 to 57.8% (95% CI 57.4% to 58.2%) in 2019. Asian and black/mixed ethnicity was associated with non-adherence (OR 1.81, 95% CI 1.56 to 2.09) as was male gender (OR 1.19, 95% CI 1.15 to 1.22), higher socioeconomic status (OR 1.60, 95% CI 1.52 to 1.68), being an ex-smoker (OR 1.12, 95% CI 1.06 to 1.19) and hypertension (OR 1.07, 95% CI 1.03 to 1.17). CONCLUSIONS: The volume and quality of DOAC prescribing has increased yearly. Future interventions to augment quality of anticoagulant management should target disparities in adherence.

Hepatitis A Vaccination Coverage Among People With Chronic Liver Disease in England (HEALD): Protocol for a Retrospective Cohort Study.

BACKGROUND: Hepatitis A outbreaks in the United Kingdom are uncommon. Most people develop mild to moderate symptoms that resolve, without sequelae, within months. However, in high-risk groups, including those with underlying chronic liver disease (CLD), hepatitis A infection can be severe, with a higher risk of mortality and morbidity. The Health Security Agency and the National Institute of Health and Care Excellence recommend preexposure hepatitis A vaccination given in 2 doses to people with CLD, regardless of its cause. There are currently no published reports of vaccination coverage for people with CLD in England or internationally. OBJECTIVE: This study aims to describe hepatitis A vaccination coverage in adults with CLD in a UK primary care setting and compare liver disease etiology, sociodemographic characteristics, and comorbidities in people who are and are not exposed to the hepatitis A vaccine. METHODS: We will conduct a retrospective cohort study with data from the Primary Care Sentinel Cohort of the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub database, which is nationally representative of the English population. We will include people aged 18 years and older who have been registered in general practices in the Research and Surveillance Centre network and have a record of CLD between January 1, 2012, and December 31, 2022, including those with alcohol-related liver disease, chronic hepatitis B, chronic hepatitis C, nonalcohol fatty liver disease, Wilson disease, hemochromatosis, and autoimmune hepatitis. We will carefully curate variables using the Systematized Nomenclature of Medicine Clinical Terms. We will report the sociodemographic characteristics of those who are vaccinated. These include age, gender, ethnicity, population density, region, socioeconomic status (measured using the index of multiple deprivation), obesity, alcohol consumption, and smoking. Hepatitis A vaccination coverage for 1 and 2 doses will be calculated using an estimate of the CLD population as the denominator. We will analyze the baseline characteristics using descriptive statistics, including measures of dispersion. Pairwise comparisons of case-mix characteristics, comorbidities, and complications will be reported according to vaccination status. A multistate survival model will be fitted to estimate the transition probabilities among four states: (1) diagnosed with CLD, (2) first dose of hepatitis A vaccination, (3) second dose of hepatitis A vaccination, and (4) death. This will identify any potential disparities in how people with CLD get vaccinated. RESULTS: The Research and Surveillance Centre population comprises over 8 million people. The reported incidence of CLD is 20.7 cases per 100,000. International estimates of hepatitis A vaccine coverage vary between 10% and 50% in this group. CONCLUSIONS: This study will describe the uptake of the hepatitis A vaccine in people with CLD and report any disparities or differences in the characteristics of the vaccinated population. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/51861.

Novel mutations of ABCA1 transporter in patients with Tangier disease and familial HDL deficiency.

The objective of the study was the characterization of ABCA1 gene mutations in 10 patients with extremely low HDL-cholesterol. Five patients (aged 6 months to 76 years) presented with splenomegaly and thrombocytopenia suggesting the diagnosis of Tangier disease (TD). Three of them were homozygous for novel mutations either in intron (c.4465-34A>G) or in exons (c.4376delT and c.5449C>T), predicted to encode truncated proteins. One patient was compound heterozygous for a nucleotide insertion (c.1758_1759insG), resulting in a truncated protein and for a nucleotide substitution c.4799A>G, resulting in a missense mutation (p.H1600R). The last TD patient, found to be heterozygous for a known mutation (p.D1009Y), had a complete defect in ABCA1-mediated cholesterol efflux in fibroblasts, suggesting the presence of a second undetected mutant allele. Among the other patients, four were asymptomatic, but one, with multiple risk factors, had severe peripheral artery disease. Three of these patients were heterozygous for known mutations (p.R130K+p.N1800H, p.R1068C, p.N1800H), while two were carriers of novel mutations (c.1195-27G>A and c.396_397insA), predicted to encode truncated proteins. The pathogenic effect of the two intronic mutations (c. 1195-27G>A and c.4465-34A>G) was demonstrated by the analysis of the transcripts of splicing reporter mutant minigenes expressed in COS-1 cells. Both mutations activated an intronic acceptor splice site which resulted in a partial intron retention in mature mRNA with the production of truncated proteins. This study confirms the allelic heterogeneity of TD and suggests that the diagnosis of TD must be considered in patients with an unexplained splenomegaly, associated with thrombocytopenia and hypocholesterolemia.

Sodium-Glucose Cotransporter-2 Inhibitor and Glucagon-Like Peptide-1 Receptor Agonist Combination Therapy in Type 2 Diabetes: Protocol for a Kidney End Points Real-world Study (COMBi-KID Study).

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are both considered to be part of standard care in the management of glycemia in type 2 diabetes. Recent trial evidence has indicated benefits on primary kidney end points for individual drugs within each medication class. Despite the potential benefits of combining SGLT2is and GLP-1RAs for glycemia management, according to national and international guideline recommendations, there is currently limited data on kidney end points for this drug combination. OBJECTIVE: The aims of the study are to assess the real-world effects of combination SGLT2i and GLP-1RA therapies for diabetes management on kidney end points, glycemic control, and weight in people with type 2 diabetes who are being treated with renin-angiotensin system blockade medication. METHODS: This retrospective cohort study will use the electronic health records of people with type 2 diabetes that are registered with general practices covering over 15 million people in England and Wales and are included in the Oxford-Royal College of General Practitioners Research and Surveillance Centre network. A propensity score-matched cohort of prevalent new users of SGLT2is and GLP-1RAs and those who have been prescribed SGLT2is and GLP-1RAs in combination will be identified. They will be matched based on drug histories, comorbidities, and demographics. A repeated-measures, multilevel, linear regression analysis will be performed to compare the mean change (from baseline) in estimated glomerular filtration rate at 12 and 24 months between those who switched to combined therapy and those continuing monotherapy with an SGLT2i or GLP-1RA. The secondary end points will be albuminuria, serum creatinine level, glycated hemoglobin level, and BMI. These will also be assessed for change at the 12- and 24-month follow-ups. RESULTS: The study is due to commence in March 2022 and is expected to be complete by September 2022. CONCLUSIONS: Our study will be the first to assess the impact of combination SGLT2i and GLP-1RA therapy in type 2 diabetes on primary kidney end points from a real-world perspective. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/34206.

Adherence to General Diabetes and Foot Care Processes, with Prompt Referral, Are Associated with Amputation-Free Survival in People with Type 2 Diabetes and Foot Ulcers: A Scottish National Registry Analysis.

Aims: To compare different packages of care across care providers in Scotland on foot-related outcomes. Methods: A retrospective cohort study with primary and secondary care electronic health records from the Scottish Diabetes Registry, including 6,845 people with type 2 diabetes and a first foot ulcer occurring between 2013 and 2017. We assessed the association between exposure to care processes and major lower extremity amputation and death. Proportional hazards were used for time-to-event univariate and multivariate analyses, adjusting for case-mix characteristics and care processes. Results were expressed in terms of hazard ratios with 95% confidence intervals. Results: 2,243 (32.7%) subjects had a major amputation or death. Exposure to all nine care processes at all ages (HR = 0.63; 95% CI: 0.58-0.69; p < .001) and higher foot care attendance in people aged >70 years (HR = 0.88; 0.78-0.99; p = .03) were associated with longer major amputation-free survival. Waiting time ≥ 12 weeks between ulceration and clinic attendance was associated with worse outcomes (HR = 1.59; 1.37-1.84; p < .001). In people > 70 years, minor amputations were associated with improved major amputation-free survival (HR = 0.69; 0.52-0.92; p = .01). Conclusions: Strict adherence to a standardised package of general diabetes care before foot ulceration, timely foot care after ulceration, and specific treatment pathways were associated with longer major amputation-free survival among a large cohort of people with type 2 diabetes in Scotland, with a larger impact on older age groups.

Long term follow up of direct oral anticoagulants and warfarin therapy on stroke, with all-cause mortality as a competing risk, in people with atrial fibrillation: Sentinel network database study.

BACKGROUND: We investigated differences in risk of stroke, with all-cause mortality as a competing risk, in people newly diagnosed with atrial fibrillation (AF) who were commenced on either direct oral anticoagulants (DOACs) or warfarin treatment. METHODS AND RESULTS: We conducted a retrospective cohort study of the Oxford Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database (a network of 500 English general practices). We compared long term exposure to DOAC (n = 5,168) and warfarin (n = 7,451) in new cases of AF not previously treated with oral anticoagulants. Analyses included: survival analysis, estimating cause specific hazard ratios (CSHR), Fine-Gray analysis for factors affecting cumulative incidence of events occurring over time and a cumulative risk regression with time varying effects.We found no difference in CSHR between stroke 1.08 (0.72-1.63, p = 0.69) and all-cause mortality 0.93 (0.81-1.08, p = 0.37), or between the anticoagulant groups. Fine-Gray analysis produced similar results 1.07 (0.71-1.6 p = 0.75) for stroke and 0.93 (0.8-1.07, p = 0.3) mortality. The cumulative risk of mortality with DOAC was significantly elevated in early follow-up (67 days), with cumulative risk decreasing until 1,537 days and all-cause mortality risk significantly decreased coefficient estimate:: -0.23 (-0.38-0.01, p = 0.001); which persisted over seven years of follow-up. CONCLUSIONS: In this large, contemporary, real world primary care study with longer follow-up, we found no overall difference in the hazard of stroke between warfarin and DOAC treatment for AF. However, there was a significant time-varying effect between anti-coagulant regimen on all-cause mortality, with DOACs showing better survival. This is a key methodological observation for future follow-up studies, and reassuring for patients and health care professionals for longer duration of therapy.

Predictors and determinants of albuminuria in people with prediabetes and diabetes based on smoking status: A cross-sectional study using the UK Biobank data.

Background: Smoking is attributed to both micro- and macrovascular complications at any stage of metabolic deregulation including prediabetes. Current global diabetes prevention programmes appear to be glucocentric, and do not fully acknowledge the ramifications of cardiorenal risk factors in smokers and ex-smokers. A more holistic approach is needed to prevent vascular complications in people with prediabetes and diabetes before and after quitting. Methods: A cross-sectional study was carried out on participants who agreed to take part in the UK Biobank dataset at the time of their first attendances between March 01, 2006, and December 31, 2010. Those who had their urinary albumin concentration (UAC) data available were included, and those who did not have this data, were excluded. A logistic regression model was fitted to explore the relationship between cardiorenal risk factors and albuminuria in people with prediabetes and diabetes, based on smoking status. Findings: A total of 502,490 participants were included in the UK Biobank dataset. Of them, 30.4% (n=152,896) had their UAC level recorded. Compared with non-smokers, the odds of albuminuria in smokers with prediabetes and diabetes were 1.21 (95% CI 1.05 - 1.39, p=0.009), and 1.26 (95% CI 1.10 - 1.44, p=0.001), respectively. The odds declined after quitting in both groups, but it was not statistically significant (p>0.05). Each unit increase in HbA1c was associated with equivalent increased odds of albuminuria in current and ex-smokers, OR 1.035 (95% CI 1.030 - 1.039, p<0.001), and 1.026 (95% CI 1.023 - 1.028, p <0.001), respectively. Compared to females, male ex-smokers were at 15% increased odds of albuminuria. In ex-smokers, each unit increase in waist circumference was associated with 1% increased risk of albuminuria. Compared with the least deprived quintiles, the odds of albuminuria in the most deprived quintiles, in current and ex-smokers were identical, OR 1.18 (95% CI 1.04-1.324, p=0.010), and 1.19 (95% CI 1.11 - 1.27, p<0.001), respectively. Interpretation: Male smokers are at a higher risk of albuminuria after smoking cessation. Monitoring waist circumference in quitters may identify those who are at a higher risk of albuminuria. Combining smoking cessation intervention in smokers with prediabetes in the current diabetes prevention programmes may offset post-cessation weight gain and reduce the risk of albuminuria. Funding: University of Sheffield.