AIMS:Sodium-glucose co-transporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have separately shown renoprotective effects in clinical trials in people with type 2 diabetes. It is unclear whether combining these agents produces incremental kidney outcome benefits. MATERIALS AND METHODS:Retrospective cohort study with a prevalent new-user design using pseudonymised data from the Oxford-Royal College of General Practitioners Research and Surveillance Centre primary care sentinel network. We extracted data for two cohorts prescribed SGLT2is and/or GLP-1 RAs between January 2013 and December 2021. We 1:1 propensity score matched SGLT2i plus GLP-1 RA combination users with monotherapy (SGLT2i or GLP-1RA) users. Multivariable linear regression analyses estimated adjusted mean differences in absolute change in estimated glomerular filtration rate (eGFR) (baseline to 1- and 2-years follow-up) between combination and monotherapy. RESULTS:Across the matched combination and SGLT2i monotherapy groups (N = 14 774), mean decline in eGFR, baseline to 1-year, was -4.5 mL/min/1.73 m2 and 2-years, -5.0 mL/min/1.73 m2, with no difference when comparing combination and SGLT2i monotherapy. Across the matched combination and GLP-1 RA monotherapy groups (N = 14 154), mean decline in eGFR, baseline to 1-year, was -5.4 mL/min/1.73 m2 and 2-years, -6.1 mL/min/1.73 m2, but combination therapy was associated with a smaller eGFR reduction compared with GLP-1 RA monotherapy (difference in eGFR at 1-year: [mean, 95% confidence interval, CI] 2.2, 1.7 to 2.8, p < 0.001; and at 2-years: 2.1, 1.4-2.7, p < 0.001). CONCLUSIONS:In real-world clinical practice, the combination of SGLT2i and GLP-1 RA may be more effective for preserving kidney function than GLP-1 RA monotherapy. This effect was not seen with combination versus SGLT2i monotherapy.

Background Structured medication reviews (SMRs) were introduced in 2020 to address polypharmacy in patients most at risk of medicines-related harm. Aim To evaluate the impact of SMRs on prescribing in primary care. Design and setting Retrospective observational cohort study of electronic health records from patients aged ≥65 years, prescribed ≥1 medications, and fulfilling the specific eligibility criteria for an SMR, registered at practices contributing data to the Oxford Clinical Informatics Digital Hub, between 1 April 2020 and 30 September 2022. Method The association between SMRs and prescription changes was examined by matching individuals who received an SMR to individuals who did not receive an SMR, according to age, sex, and primary care practice, using cumulative density sampling. Analyses were undertaken using adjusted logistic regression. Results Of 635 698 eligible patients, 82 285 (12.9%, 95% confidence interval [CI] = 12.9 to 13.0) received ≥1 SMR during the study observation period. In those prescribed potentially inappropriate drug combinations prior to an SMR, between 12.5% and 40.0% were corrected up to 3 months later. In matched analyses, SMRs were most strongly associated with an increase in new prescriptions of angiotensin-converting enzyme inhibitors (adjusted odds ratio [aOR] 1.56, 95% CI = 1.35 to 1.81), statins (aOR 1.78, 95% CI = 1.57 to 2.02), and antidepressants (aOR 1.45, 95% CI = 1.28 to 1.63). SMRs were also most strongly associated with stopping these drug classes in those previously prescribed treatment. Conclusion SMRs were associated with starting new medications and stopping existing prescriptions compared with usual care. Further work is needed to understand if these changes improved patient outcomes.

BACKGROUND:Structured medication reviews (SMRs) were introduced into primary care in England in 2020 for patients living with multiple long-term conditions (MLTC), polypharmacy, increased frailty, in care homes, or at risk of medicines-related harm. SMRs aim to optimise the therapeutic potential of medication and reduce medicine-related harms through holistic reviews. AIM:To explore the day-to-day work being undertaken with, and by, clinical pharmacists to implement, embed, and integrate SMRs into practice, and consider how to optimise SMRs. DESIGN AND SETTING:Qualitative one-to-one interviews with clinical pharmacists undertaking SMRs and SMR service leaders/managers (SMR leads) in England between February 2023 and November 2024. METHOD:Participants were recruited as part of a wider evaluation of the roll-out of SMRs in England. Interview topic guides and qualitative data analysis were informed by normalisation process theory. RESULTS:Eighteen clinical pharmacists and five SMR leads participated. Participants reported often having to explain the purpose of SMRs and clinical pharmacists' roles to patients, partly owing to patients not being informed about SMRs. Participants valued SMRs and expressed that trust-building and tailored consultations were important for optimising medications. Integration of SMRs into routine practice varied because of high workload, inconsistent leadership support, inadequate administrative/pharmacist technician resource, and lack of training. However, participants described SMRs as valuable for identifying and addressing unmet needs and supporting holistic, person-centred care across MLTC pathways. CONCLUSION:The findings demonstrate the need for improved information on SMRs for patients and primary care teams, adequate and appropriate resource allocation, and enhanced support for consultation skills training to optimise medicines use.

Objectives: The present study aimed to evaluate the impact of structured medication reviews (SMRs), by examining the proportion of eligible patients who received a review in the first two years of the programme, and whether SMRs were associated with changes in prescribing. Design: Retrospective observational cohort study. Setting: Patients registered to primary care practices in England contributing data to the Oxford Clinical Informatics Digital Hub (ORCHID) were included between 1 st April 2020 and 30 th September 2022. Participants: De-identified data were extracted from the electronic health records of individuals registered to ORCHID practices aged ≥65 years, prescribed one or more medications and fulfilling the specific eligibility criteria for a SMR. Main outcome measures: The primary outcome was the proportion of patients who received a review. Further outcomes included the proportion of potentially inappropriate drug combinations corrected following an SMR. The association between SMRs and prescription changes and primary care contacts was examined by matching individuals who received an SMR to individuals who did not receive an SMR, according to age, sex and primary care practice using cumulative density sampling. Analyses were undertaken using adjusted logistic regression. Results: From a total of 635,698 eligible patients, 82,285 patients (12.94%, 95% confidence interval [CI] 12.86% to 13.02%) received at least one SMR during the study observation period. In those prescribed potentially inappropriate drug combinations prior to an SMR, between 12.5% and 40.0% were corrected up to three months later. In matched analyses, SMRs were associated with a significant increase new prescriptions of ACE inhibitors (adjusted odds ratio [aOR] 1.56, 95%CI 1.35-1.81), statins (aOR 1.78, 95%CI 1.57-2.02), inhaled corticosteroids (aOR 1.19 95%CI 1.05-1.36), opioids (aOR 1.31 95%CI 1.20-1.42), and antidepressants (aOR 1.45 95%CI 1.28-1.63). In those previously prescribed treatment, individuals receiving an SMR were significantly more likely stop ACE inhibitors (aOR 1.37, 95%CI 1.18-1.58), statins (aOR 1.35, 95%CI 1.17-1.56) and antidepressants (antidepressants aOR 1.37 95%CI 1.21-1.56). SMRs were associated with a significant increase in primary care contacts of 0.14 (95% CI 0.13 to 0.16; equivalent to 14 extra patient contacts for every 100 individuals receiving an SMR). Conclusions: SMRs were associated with starting new medications and stopping existing prescriptions compared to usual care. It was unclear if such activity was appropriate or represented improved patient care. Further work is needed to understand if these changes in prescribing improved patient outcomes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by the National Institute for Health Research (NIHR) Applied Research Collaboration Multiple Long-term Conditions Cross-ARC collaboration. JPS received funding from the Wellcome Trust/Royal Society via a Sir Henry Dale Fellowship (ref: 211182/Z/18/Z), and now receives funding via an NIHR Advanced Fellowship (NIHR303621). RB receives funding via an NIHR Advanced Fellowship (NIHR302557). FDRH, RM and KT were supported by NIHR Applied Research Collaboration Oxford and the Thames Valley (OxTV-ARC). RM is an NIHR Senior Investigator. KK and SS are supported by the NIHR Applied Research Collaboration East Midlands (ARC EM), NIHR Global Research Centre for Multiple Long Term Conditions, NIHR Cross NIHR Collaboration for Multiple Long Term Conditions, NIHR Leicester Biomedical Research Centre (BRC) and the British Heart Foundation (BHF) Centre of Excellence. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was approved by South Central Hampshire A Research Ethics Committee (ref 22/SC/0373). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Requests for data sharing should be made directly to the Primary Care Hosted Research Datasets Independent Scientific Committee (PrimDISC), based at the University of Oxford. Code lists used to define variables included in the dataset are available at https://github.com/ndpchs-cprd/PD-0002-2022-OSCAR.

BACKGROUND:International guidelines recommend the administration of two doses of pre-exposure hepatitis A vaccination for people with chronic liver disease to prevent severe complications. We aimed to describe hepatitis A vaccination coverage and mortality in adults with chronic liver disease in England. METHODS:We did a retrospective cohort study using routinely collected medical record data from the Oxford-Royal College of General Practitioners Research and Surveillance Centre (RSC) primary care sentinel network. We included people aged 18 years or older who were diagnosed with chronic liver disease between Jan 1, 2012, and Dec 31, 2022. The primary outcome of interest was hepatitis A vaccination. Hepatitis A vaccination coverage was calculated using the number of vaccinated people with chronic liver disease as the numerator and the chronic liver disease population in the RSC dataset as the denominator. We compared individual characteristics by vaccination status using descriptive statistics. We used a multistate survival model to estimate the transition probabilities between four states: (1) diagnosis of chronic liver disease; (2) first hepatitis A vaccination; (3) second hepatitis A vaccination; and (4) death. FINDINGS:664 571 individuals aged 18 years or older with chronic liver disease were identified from the RSC sentinel network population, of whom 625 079 individuals were included in our analysis. Of 625 079 individuals with chronic liver disease, 13 875 (2·2%) had received a first hepatitis A vaccination, 3007 (0·4%) had received a second dose, 732 (5·3%) of 13 875 vaccinated individuals died, and 101 065 (16·5%) of 611 204 individuals without vaccination died during the study period. Adjusting for death as a competing risk, vaccination was more likely among younger age quintiles (hazard ratio 5·46 [95% CI 5·13-5·81]), non-smokers (1·59 [1·54-1·65]), residents of urban areas (1·28 [1·21-1·35]), individuals with higher socioeconomic status (1·06 [1·03-1·10]), and individuals with a diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD; 1·71 [1·64-1·78]). Individuals with a history of harmful alcohol use (0·36 [0·32-0·39]), type 1 diabetes (0·46 [0·36-0·57]), chronic kidney disease (0·63 [0·57-0·70]), or mental disorders (0·66 [0·64-0·69]) were less likely to be vaccinated. The lowest risk of mortality was in people with chronic liver disease of infectious or autoimmune aetiology and in people with MASLD. INTERPRETATION:Hepatitis A vaccine uptake among people with chronic liver disease in England is low, with disparities by age, location (urban vs rural), and socioeconomic status. Steps should be taken to reduce the inequalities in vaccine administration. FUNDING:GlaxoSmithKline's Investigator Sponsored Studies Program.

OBJECTIVE:COVID-19 vaccine surveillance detected thrombotic thrombocytopenia syndrome (TTS), a rare combination of thrombosis and thrombocytopenia, after COVID-19 vaccination. We evaluated TTS risk within 28 days of AZD1222 and BNT162b2 exposure. METHODS:Matched case-control (MCCS) and self-controlled case series (SCCS) studies used Oxford-Royal College of General Practitioners Research and Surveillance Centre data linked to immunization, hospitalization and death data. English patient records extracted from December 2, 2020 to October 31, 2022 were used to identify TTS cases and age, sex, and practice matched controls. Conditional logistic regression and conditional Poisson regression were used for MCCS and SCCS analyses, respectively. RESULTS:Of 666 TTS events identified, >90% happened without AZD1222/BNT162b2 exposure in the preceding 28 days. MCCS analyses showed no association between TTS and a composite of both first and second AZD1222 dose (adjusted odds ratio [aOR]: 1.45 [95% CI: 0.90-2.34]). Both studies showed increased TTS risk after AZD1222 first dose (MCCS, aOR: 2.12 [1.14-3.92]; SCCS, incidence rate ratio: 3.49 [2.22-5.49]). No association between TTS and BNT162b2 was observed. CONCLUSION:Consistent with previous studies, we found an association between TTS and receiving a first dose of AZD1222. There were no associations of TTS with AZD1222 second dose and BNT162b2 first or second doses.

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 similar to 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. (c) 2024 The Author(s). Published by Elsevier Ltd on behalf of The British Infection Association.

Background. 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 generalizability to those without co-existing type 2 diabetes (T2D), and the representativeness of the Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY) trial has not been adequately explored. We hypothesized 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 Informatics 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 Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), Dapagliflozin and Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease (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 with the real-world CKD population (32.8%). Renin-angiotensin system inhibitors were prescribed in almost all trial participants, compared with 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 subgroup of people with CKD at high risk of adverse kidney events. Our 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.

Abstract Background and Aims Observational studies suggest that sodium-glucose co-transporter-2 (SGLT2) inhibitor kidney outcome trials are not representative 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 representativeness of the EMPA-KIDNEY trial. Method 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 database. The proportions of people with CKD 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, including 32.8% (n = 169 443) with co-existing T2D. In the total CKD cohort, 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 trial eligible populations, 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 total CKD population (32.8%). Renin-angiotensin-aldosterone system inhibitors were prescribed in almost all trial participants compared to less than half of the total CKD population. Females were underrepresented and less likely to be eligible for the trials. Conclusion SGLT2 inhibitor kidney outcome trials are not representative of most people with CKD in English Primary Care. These findings highlight the importance of complementing trials with real-world studies, exploring the effectiveness of SGLT2 inhibitors in the broader population of people with CKD treated in routine clinical practice.

Objective To evaluate Phenotype Execution and Modelling Architecture (PhEMA), to express sharable phenotypes using Clinical Query Language (CQL) and intensional SNOMED CT Fast Healthcare Interoperability Resources (FHIR) valuesets, for exemplar chronic disease, sociodemographic risk factor and surveillance phenotypes. Method We curated three phenotypes: Type 2 diabetes (T2DM), excessive alcohol use and incident influenza-like illness (ILI) using CQL to define clinical and administrative logic. We defined our phenotypes with valuesets, using SNOMED’s hierarchy and expression constraint language (ECL), and CQL, combining valuesets and adding temporal elements where needed. We compared the count of cases found using PhEMA with our existing approach using convenience datasets. Results The T2DM phenotype could be defined as two intensionally defined SNOMED valuesets and a CQL script. It increased the prevalence from 7.2% to 7.3%. Excess alcohol phenotype was defined by valuesets that added qualitative clinical terms to the quantitative conceptual definitions we currently use; this change increased prevalence by 58%, from 1.2% to 1.9%. We created an ILI valueset with SNOMED concepts, adding a temporal element using CQL to differentiate new episodes. This increased the weekly incidence in our convenience sample (weeks 26 to 38) from 0.95 cases to 1.11 cases per 100,000 people. Conclusions Phenotypes for surveillance and research can be described fully and comprehensibly using CQL and intensional FHIR valuesets. Our use case phenotypes identified a greater number of cases, whilst anticipated from excessive alcohol this was not for our other variable. This may have been due to our use of SNOMED CT hierarchy.

Summary: 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.

Abstract Background and Aims 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. Method We performed a cross-sectional study of adults with CKD registered with primary care practices in the Oxford-Royal College of General Practitioners Research and Surveillance Centre network on the 31st December 2022. We examined the extent to which SGLT2 inhibitor guidelines apply to and are then implemented in adults with CKD. We used a logistic regression model to identify independent factors associated with SGLT2 inhibitor prescribing. Results 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 CKD patients with 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 0·70, 95% CI 0·67-0·72, p < 0·001), individuals of Black ethnicity (OR 0·87, 95% CI 0·79-0·95, p < 0·001) and those of lower socio-economic status (OR 0·71, 95% CI 0·68-0·75, p < 0.001) 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 < 0·001, eGFR 30-45 mL/min/1·73 m2 OR 0·73, 95% CI 0·69-0·78, p < 0·001, eGFR 15-30 mL/min/1·73 m2 OR 0·52, 95% CI 0·46-0·60, p < 0·001, eGFR <15 mL/min/1·73 m2 OR 0·03, 95% CI 0·00-0·23, p = 0·004, 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 < 0·001). Conclusion SGLT2 inhibitor guidelines in CKD have not yet been successfully implemented into clinical practice, most notably in those without co-existing T2D. 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.

Background Post-authorisation vaccine safety surveillance is well established for reporting common adverse events of interest (AEIs) following influenza vaccines, but not for COVID-19 vaccines. Aim To estimate the incidence of AEIs presenting to primary care following COVID-19 vaccination in England, and report safety profile differences between vaccine brands. Methods We used a self-controlled case series design to estimate relative incidence (RI) of AEIs reported to the national sentinel network, the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub. We compared AEIs (overall and by clinical category) 7 days pre- and post-vaccination to background levels between 1 October 2020 and 12 September 2021. Results Within 7,952,861 records, 781,200 individuals (9.82%) presented to general practice with 1,482,273 AEIs, 4.85% within 7 days post-vaccination. Overall, medically attended AEIs decreased post-vaccination against background levels. There was a 3–7% decrease in incidence within 7 days after both doses of Comirnaty (RI: 0.93; 95% CI: 0.91–0.94 and RI: 0.96; 95% CI: 0.94–0.98, respectively) and Vaxzevria (RI: 0.97; 95% CI: 0.95–0.98). A 20% increase was observed after one dose of Spikevax (RI: 1.20; 95% CI: 1.00–1.44). Fewer AEIs were reported as age increased. Types of AEIs, e.g. increased neurological and psychiatric conditions, varied between brands following two doses of Comirnaty (RI: 1.41; 95% CI: 1.28–1.56) and Vaxzevria (RI: 1.07; 95% CI: 0.97–1.78). Conclusion COVID-19 vaccines are associated with a small decrease in medically attended AEI incidence. Sentinel networks could routinely report common AEI rates, contributing to reporting vaccine safety.

OBJECTIVES To estimate the incidence of adverse events of interest (AEIs) after receiving their first and second doses of coronavirus disease 2019 (COVID-19) vaccinations, and to report the safety profile differences between the different COVID-19 vaccines. DESIGN We used a self-controlled case series design to estimate the relative incidence (RI) of AEIs reported to the Oxford-Royal College of General Practitioners national sentinel network. We compared the AEIs that occurred seven days before and after receiving the COVID-19 vaccinations to background levels between 1 October 2020 and 12 September 2021. SETTING England, UK. PARTICIPANTS Individuals experiencing AEIs after receiving first and second doses of COVID-19 vaccines. MAIN OUTCOME MEASURES AEIs determined based on events reported in clinical trials and in primary care during post-license surveillance. RESULTS A total of 7,952,861 individuals were vaccinated with COVID-19 vaccines within the study period. Among them, 781,200 individuals (9.82%) presented to general practice with 1,482,273 AEIs. Within the first seven days post-vaccination, 4.85% of all the AEIs were reported. There was a 3-7% decrease in the overall RI of AEIs in the seven days after receiving both doses of Pfizer-BioNTech BNT162b2 (RI = 0.93; 95% CI: 0.91-0.94) and 0.96; 95% CI: 0.94-0.98), respectively) and Oxford-AstraZeneca ChAdOx1 (RI = 0.97; 95% CI: 0.95-0.98) for both doses), but a 20% increase after receiving the first dose of Moderna mRNA-1273 (RI = 1.20; 95% CI: 1.00-1.44)). CONCLUSIONS COVID-19 vaccines are associated with a small decrease in the incidence of medically attended AEIs. Sentinel networks could routinely report common AEI rates, which could contribute to reporting vaccine safety.

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.

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.

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.