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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Barriers and Facilitators to the Initiation of Injectable Therapies for Type 2 Diabetes Mellitus: A Mixed Methods Study.

INTRODUCTION: Initiation of injectable therapies in type 2 diabetes (T2D) is often delayed, however the reasons why are not fully understood. METHODS: A mixed methods study performed in sequential phases. Phase 1: focus groups with people with T2D (injectable naïve [n = 12] and experienced [n = 5]) and healthcare professionals (HCPs; nurses [n = 5] and general practitioners (GPs) [n = 7]) to understand their perceptions of factors affecting initiation of injectables. Phase 2: video-captured GP consultations (n = 18) with actor-portrayed patient scenarios requiring T2D treatment escalation to observe the initiation in the clinical setting. Phase 3: HCP surveys (n = 87) to explore external validity of the themes identified in a larger sample. RESULTS: Focus groups identified patients' barriers to initiation; fear, lack of knowledge and misconceptions about diabetes and treatment aims, concerns regarding lifestyle restrictions and social stigma, and feelings of failure. Facilitators included education, good communication, clinician support and competence. HCP barriers included concerns about weight gain and hypoglycaemia, and limited consultation time. In simulated consultations, GPs performed high-quality consultations and recognised the need for injectable initiation in 9/12 consultations where this was the expert recommended option but did not provide support for initiation themselves. Survey results demonstrated HCPs believe injectable initiation should be performed in primary care, although many practitioners reported inability to do so or difficulty in maintaining skills. CONCLUSION: People with T2D have varied concerns and educational needs regarding injectables. GPs recognise the need to initiate injectables but lack practical skills and time to address patient concerns and provide education. Primary care nurses also report difficulties in maintaining these skills. Primary care HCPs initiating injectables require additional training to provide practical demonstrations, patient education and how to identify and address concerns. These skills should be concentrated in the hands of a small number of primary care providers to ensure they can maintain their skills.

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.

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.

Developing a Long COVID Phenotype for Postacute COVID-19 in a National Primary Care Sentinel Cohort: Observational Retrospective Database Analysis.

BACKGROUND: Following COVID-19, up to 40% of people have ongoing health problems, referred to as postacute COVID-19 or long COVID (LC). LC varies from a single persisting symptom to a complex multisystem disease. Research has flagged that this condition is underrecorded in primary care records, and seeks to better define its clinical characteristics and management. Phenotypes provide a standard method for case definition and identification from routine data and are usually machine-processable. An LC phenotype can underpin research into this condition. OBJECTIVE: This study aims to develop a phenotype for LC to inform the epidemiology and future research into this condition. We compared clinical symptoms in people with LC before and after their index infection, recorded from March 1, 2020, to April 1, 2021. We also compared people recorded as having acute infection with those with LC who were hospitalized and those who were not. METHODS: We used data from the Primary Care Sentinel Cohort (PCSC) of the Oxford Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database. This network was recruited to be nationally representative of the English population. We developed an LC phenotype using our established 3-step ontological method: (1) ontological step (defining the reasoning process underpinning the phenotype, (2) coding step (exploring what clinical terms are available, and (3) logical extract model (testing performance). We created a version of this phenotype using Protégé in the ontology web language for BioPortal and using PhenoFlow. Next, we used the phenotype to compare people with LC (1) with regard to their symptoms in the year prior to acquiring COVID-19 and (2) with people with acute COVID-19. We also compared hospitalized people with LC with those not hospitalized. We compared sociodemographic details, comorbidities, and Office of National Statistics-defined LC symptoms between groups. We used descriptive statistics and logistic regression. RESULTS: The long-COVID phenotype differentiated people hospitalized with LC from people who were not and where no index infection was identified. The PCSC (N=7.4 million) includes 428,479 patients with acute COVID-19 diagnosis confirmed by a laboratory test and 10,772 patients with clinically diagnosed COVID-19. A total of 7471 (1.74%, 95% CI 1.70-1.78) people were coded as having LC, 1009 (13.5%, 95% CI 12.7-14.3) had a hospital admission related to acute COVID-19, and 6462 (86.5%, 95% CI 85.7-87.3) were not hospitalized, of whom 2728 (42.2%) had no COVID-19 index date recorded. In addition, 1009 (13.5%, 95% CI 12.73-14.28) people with LC were hospitalized compared to 17,993 (4.5%, 95% CI 4.48-4.61; P<.001) with uncomplicated COVID-19. CONCLUSIONS: Our LC phenotype enables the identification of individuals with the condition in routine data sets, facilitating their comparison with unaffected people through retrospective research. This phenotype and study protocol to explore its face validity contributes to a better understanding of LC.

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.

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.

The Effect of the COVID-19 Pandemic on Glycemic Monitoring and Other Processes of Care for Type 2 Diabetes: Protocol for a Retrospective Cohort Study.

BACKGROUND: Social distancing and other nonpharmaceutical interventions to reduce the spread of COVID-19 infection in the United Kingdom have led to substantial changes in delivering ongoing care for patients with chronic conditions, including type 2 diabetes mellitus (T2DM). Clinical guidelines for the management and prevention of complications for people with T2DM delivered in primary care services advise routine annual reviews and were developed when face-to-face consultations were the norm. The shift in consultations from face-to-face to remote consultations caused a reduction in direct clinical contact and may impact the process of care for people with T2DM. OBJECTIVE: The aim of this study is to explore the impact of the COVID-19 pandemic's first year on the monitoring of people with T2DM using routine annual reviews from a national primary care perspective in England. METHODS: A retrospective cohort study of adults with T2DM will be performed using routinely collected primary care data from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC). We will describe the change in the rate of monitoring of hemoglobin A1c (HbA1c) between the first year of the COVID-19 pandemic (2020) and the preceding year (2019). We will also report any change in the eight checks that make up the components of these reviews. The change in HbA1c monitoring rates will be determined using a multilevel logistic regression model, adjusting for patient and practice characteristics, and similarly, the change in a composite measure of the completeness of all eight checks will be modeled using ordinal regression. The models will be adjusted for the following patient-level variables: age, gender, socioeconomic status, ethnicity, COVID-19 shielding status, duration of diabetes, and comorbidities. The model will also be adjusted for the following practice-level variables: urban versus rural, practice size, Quality and Outcomes Framework achievement, the National Health Service region, and the proportion of face-to-face consultations. Ethical approval was provided by the University of Oxford Medical Sciences Interdivisional Research Ethics Committee (September 2, 2021, reference R77306/RE001). RESULTS: The analysis of the data extract will include 3.96 million patients with T2DM across 700 practices, which is 6% of the available Oxford-RCGP RSC adult population. The preliminary results will be submitted to a conference under the domain of primary care. The resulting publication will be submitted to a peer-reviewed journal on diabetes and endocrinology. CONCLUSIONS: The COVID-19 pandemic has impacted the delivery of care, but little is known about the process of caring for people with T2DM. This study will report the impact of the COVID-19 pandemic on these processes of care. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35971.

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.

Dashboards to reduce inappropriate prescribing of metformin and aspirin: A quality assurance programme in a primary care sentinel network.

AIMS: To pilot two dashboards to monitor prescribing of metformin and aspirin according to the National Institute for Health and Care Excellence (NICE) 'Do-Not-Do' recommendations. METHODS: This quality assurance programme was conducted in twelve general practices of the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network. We developed dashboards to flag inappropriate prescribing of metformin and aspirin to people with type 2 diabetes mellitus (T2DM). In Phase 1, six practices (Group A) received a dashboard flagging suboptimal metformin prescriptions in people with reduced renal function. The other six practices (Group B) were controls. In Phase 2, Group B were provided a dashboard to flag inappropriate aspirin prescribing and Group A were controls. We used logistic regression to explore associations between dashboard exposure and inappropriate prescribing. RESULTS: The cohort comprised 5644 individuals (Group A, n = 2656; Group B, n = 2988). Half (51.6%, n = 2991) were prescribed metformin of which 15 (0.5%) were inappropriate (Group A, n = 10; Group B, n = 5). A fifth (17.6%, n = 986) were prescribed aspirin of which 828 (84.0%) were inappropriate. During Phase 1, metformin was stopped in 50% (n = 5) of people in Group A, compared with 20% (n = 1) in the control group (Group B); in Phase 2, the odds ratio of inappropriate aspirin prescribing was significantly lower in practices that received the dashboard versus control (0.44, 95%CI 0.27-0.72). CONCLUSIONS: It was feasible to use a dashboard to flag inappropriate prescribing. Whilst underpowered to report a change in metformin, we demonstrated a reduction in inappropriate aspirin prescribing.