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Background: The vascular endothelium is a novel target for the detection, management, and prevention of doxorubicin (DOX)-induced cardiotoxicity. Objectives: The study aimed to: 1) develop a methodology by computed tomography angiography (CTA) to evaluate stress-induced changes in epicardial coronary diameter; and 2) apply this to a chronic canine model of DOX-induced cardiotoxicity to assess vascular toxicity. Methods: To develop and validate quantitative methods, sequential retrospectively gated coronary CTAs were performed in 16 canines. Coronary diameters were measured at prespecified distances during rest, adenosine (ADE) (280 μg/kg/min), rest 30 min post-ADE, and dobutamine (DOB) (5 μg/kg/min). A subgroup of 8 canines received weekly intravenous DOX (1 mg/kg) for 12 to 15 weeks, followed by rest-stress CTA at cumulative doses of ∼4-mg/kg (3 to 5 mg/kg), ∼8-mg/kg (7 to 9 mg/kg), and ∼12-mg/kg (12 to 15 mg/kg) of DOX. Echocardiograms were performed at these timepoints to assess left ventricular ejection fraction and global longitudinal strain. Results: Under normal conditions, epicardial coronary arteries reproducibly dilated in response to ADE (left anterior descending coronary artery [LAD]: 12 ± 2%, left circumflex coronary artery [LCx]: 13 ± 2%, right coronary artery [RCA]: 14 ± 2%) and DOB (LAD: 17 ± 3%, LCx: 18 ± 2%, RCA: 15 ± 3%). With DOX, ADE vasodilator responses were impaired after ∼4-mg/kg (LAD: –3 ± 1%, LCx: 0 ± 2%, RCA: –5 ± 2%) and ∼8-mg/kg (LAD: –3 ± 1%, LCx: 0 ± 1%, RCA: –2 ± 2%). The DOB dilation response was preserved at ∼4-mg/kg of DOX (LAD: 18 ± 4%, LCx: 11 ± 3%, RCA: 11 ± 2%) but tended to decrease at ∼8-mg/kg of DOX (LAD: 4 ± 2%, LCx: 8 ± 3%, RCA: 3 ± 2%). A significant left ventricular ejection fraction reduction was observed only at 12 to 15 mg/kg DOX (baseline: 63 ± 2%, 12-mg/kg: 45 ± 3%). Global longitudinal strain was abnormal at ∼4-mg/kg of DOX (p = 0.011). Conclusions: CTA can reliably assess epicardial coronary diameter in response to pharmacological stressors, providing a noninvasive functional index of coronary vasoreactivity. Impaired epicardial vasodilation occurs early in DOX-induced cardiotoxicity.

Background and Aims: The wnt signaling pathway regulates adipogenesis and insulin secretion. The WNT5B gene has been reported to confer susceptibility to type 2 diabetes (T2D) in the Japanese population, and we therefore evaluated this in Caucasian subjects with respect to obesity status.Methods and Results: Two thousand seven hundred and one Caucasian middle-aged men from the prospective Northwick Park Heart Study II (NPHSII) of whom 153 developed T2D over 15 years and 1268 Caucasian middle-aged patients with T2D (60% male) were genotyped using a TaqMan assay for the IVS3C>G variant (rs2270031) in the WNT5B gene. The frequency of the G allele was 0.026 (0.022-0.031) in controls and 0.031 (0.025-0.039) in patients with diabetes, p=0.24. In the prospective analysis, G allele carriers with BMI below 26 kg/m(2) had significantly higher T2D hazard risk [3.46 (1.34-8.96), p=0.01]. Comparing T2D cases with NPHSII controls, the G allele was associated with a significantly higher T2D odds ratio (OR) of 1.50 (1.06-2.12), p=0.02 in subjects with BMI lower than 30 kg/m(2). Increasing BMI had a smaller effect on risk in G allele carriers. The effect on risk was not explained by genotype being associated with any classical T2D risk factor. When the combined effect of this SNP and the TCF7L2 IVS3C>T SNP (rs7903146) was evaluated, a 2.07 (1.40-3.07), p<0.0001 fold higher OR was observed in carriers of both the rare alleles.Conclusion: Variation in WNT5B predisposes to T2D in the absence of obesity. The increase in risk conferred by the presence of both WNT5B and TCF7L2 variants strengthens the role of wnt signaling in T2D. [ABSTRACT FROM AUTHOR]

Efforts to improve glycaemic control in people with diabetes have encourage more intensive therapeutic approaches. Hypoglycaemia is a risk associated with insulin therapy and a further consequence of intensified treatment is unwanted weight gain. The introduction of the long-acting insulin analogues, glargine and detemir, has provided a circulating insulin profile more reminiscent of normal basal insulin. This has allowed insulin dose escalation with a reduced risk of hypoglycaemia. The current study investigates the effect of switching treatment to insulin detemir in patients who had gained weight on insulin glargine therapy. Two months of treatment with insulin determir did not alter glycaemic control or insulin dosage, but body weight was significantly reduced in patients with type 1 (p<0.05) and type 2 (p<0.005) diabetes. [ABSTRACT FROM AUTHOR]

Advances in drug formulation have improved the tolerability of many commonly used agents. Metformin is recommended as initial drug therapy for type 2 diabetes and has proven long-term efficacy and safety. However, gastrointestinal (GI) side-effects of standard, immediate-release (IR) metformin often reduce medication adherence and limit dose titration. A prolonged-release metformin formulation may improve tolerability over its IR counterpart. We report the results of two prospective and two retrospective clinic-based evaluations of the tolerability of metformin in a total of 95 patients intolerant to standard IR metformin assessed over three to six months following a switch from IR to prolonged-release metformin (Glucophage® SR). Between 62% and 100% of patients from the centres tolerated the prolonged-release formulation. Glycaemia following the switch was improved or unchanged. Prolonged-release metformin represents a useful option for patients intolerant of standard IR metformin due to GI side-effects. This improved tolerance of prolonged-release metformin may improve medication adherence and thereby enhance treatment outcomes. [ABSTRACT FROM AUTHOR]

The rising incidence of type 2 diabetes in the developed world is already well established. There are, however, specific populations in the occident where there is an increase in type 2 diabetes, but unrelated to obesity. One such group is the HIV infected population. Associated with this increase in diabetes, there has been a similar rise in cardiovascular disease. This review article aims to outline the aetiological factors that may precipitate diabetes and cardiovascular disease in this group, and establishes the role of a specialist diabetes and HIV clinic in the management of these individuals. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

AIM: To determine the association between coronary calcification score (CACS) obtained by electron beam computed tomography (EBCT) and cardiovascular risk factors in Type 2 diabetic subjects entered into a prospective cohort study. METHODS: Type 2 diabetic subjects attending routine hospital diabetic clinics without known coronary heart disease (CHD) underwent EBCT to measure CACS. Demographic data were obtained and conventional cardiovascular risk factors were measured at baseline. RESULTS: Four hundred and ninety-five subjects were assessed of whom 67.7% were male. They had a mean (SD) age of 62.9 (7.1) years, with median (inter-quartile range) duration of diabetes of 8 (4-13) years. None had a history of coronary artery disease. Forty-five per cent were receiving lipid-lowering agents (including 36% statins). In a univariate analysis, there were significant associations between increased CACS and age, duration of diabetes, male gender, waist-hip ratio (WHR), systolic blood pressure, and the use of statins. In a multivariate model adjusting for the possible interaction of these and other factors, the significant association between CACS and WHR, systolic blood pressure, male gender and statin use remained. CONCLUSIONS: The close association between CACS and WHR and the association with systolic blood pressure suggest that coronary calcification may be particularly linked to the metabolic syndrome in Type 2 diabetes. [ABSTRACT FROM AUTHOR]

Precise blood pressure (BP) measurements are an important part of the clinical assessment of patients with diabetes, and may be influenced by patient and observer-related factors. Several 'stress' events specific to the diabetes clinic may influence the BP including the finger prick for capillary blood glucose measurement and the consultation with a doctor. Semi-automated oscillometric devices may be helpful in the diabetes clinic as these not only allow for multiple measurements to be obtained easily but may also reduce observer errors.The aims of this study were to assess BP changes during specific 'stress' events and to evaluate the role of a semi-automated BP device (Omron HEM-705CP) in the diabetes clinic.Fifty-one routine follow-up patients (35 men and 16 women) participated in this diabetes clinic-based observational study. Mean BP mmHg (+/-SD) were: on arrival to the clinic 143/84 (26/12); pre-finger prick 141/83 (24/11); post-finger prick 141/81 (24/11); pre-doctor consultation 142/81 (23/14); post-doctor consultation 142/82 (23/13); end of the clinic 146/84 (24/17); 15 minutes after clinic 140/79 (22/10). There were no significant differences, as assessed by single ANOVA, in either systolic or diastolic BP recordings.There appears to be no significant alerting response related to potential stress events in a diabetes clinic and BP can be measured at any stage using the Omron HEM-705CP. [ABSTRACT FROM AUTHOR]

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

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 m 2 had a lower likelihood of receiving an SGLT2 inhibitor, compared to those with an eGFR ≥60 mL/min/1.73 m 2 (eGFR 45-60 mL/min/1.73 m 2 OR 0.65, 95% CI 0.62-0.68, p <0.0001, eGFR 30-45 mL/min/1.73 m 2 OR 0.73, 95% CI 0.69-0.78, p <0.0001, eGFR 15-30 mL/min/1.73 m 2 OR 0.52, 95% CI 0.46-0.60, p <0.0001, eGFR <15 mL/min/1.73 m 2 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., Competing Interests: AF, WE, MJ, JM, XF and NC declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. WH has had part of his academic salary funded from grant awards with Eli Lilly and Co., Novo Nordisk Ltd, AstraZeneca UK Ltd and Merck Sharp & Dohme Ltd. WH has no other relationships or activities that could appear to have influenced the submitted work. MF was awarded a grant from Merck Sharp & Dohme Ltd through the Nuffield Department of Primary Care Health Sciences, University of Oxford for an investigator led diabetes project unrelated to this study. MF has received personal speaker fees from Sanofi. MF has no other relationships or activities that could appear to have influenced the submitted work. DB was awarded grants through St George's University of London for NIHR portfolio studies in nephrology and cardiology, unrelated to this study, from AstraZeneca Externally Sponsored Scientific Research, Kidney Research UK, South-West London ICS Innovation Fund, and the Canadian Institute of Healthcare Research. DB has received consulting fees from Bayer, and payment for presentations from Bayer and Vifor Pharma. DB has received payment for sitting on an Advisory Board for the ORCHID and ADOPTION randomised controlled trials. DB has no other relationships or activities that could appear to have influenced the submitted work. RS is an unpaid trustee of the Blood Pressure Association. RS has no other relationships or activities that could appear to have influenced the submitted work. SdeL has received grants through the Nuffield Department of Primary Care Health Sciences, University of Oxford for investigator led studies in diabetes and cardio-metabolic disease, unrelated to this study, from GSK, Eli Lilly and Co., Novo Nordisk Ltd, Sanofi, and Merck Sharp & Dohme Ltd. SdeL has no other relationships or activities that could appear to have influenced the submitted work. PS received honoraria for presentations from AstraZeneca Ltd and Bayer Ltd. She received financial support from Bayer Ltd to attend the American Society of Nephrology Conference 2022 and Pharmacosmos to attend the European Renal Association Annual Scientific Meeting 2023. PS sits on the Executive Committee and is a trustee of the British & Irish Hypertension Society and Blood Pressure UK, which are all unpaid positions. PS has no other relationships or activities that could appear to have influenced the submitted work., (© 2024 The Authors.)

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., (© 2023 John Wiley & Sons Ltd.)

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., (© 2022 John Wiley & Sons Ltd.)

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., (Copyright © 2021 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Objective: To investigate the association between Raynaud phenomenon (RP) and coronary microvascular dysfunction, we measured myocardial flow reserve (MFR) using positron emission tomography/computed tomography (PET/CT) in patients with primary and secondary RP and controls., Methods: Patients with RP, patient controls, and healthy participants who underwent dynamic rest-stress 82-rubidium PET/CT were studied. Differences in heart rate-blood pressure product-corrected MFR and clinical predictors of reduced MFR (< 2.0) were determined., Results: Forty-nine patients with RP (80% female; aged 65 ± 11 yrs; 11 with primary RP, 18 with systemic sclerosis [SSc], and 20 with other autoimmune rheumatic diseases [AIRDs] including 6 with systemic lupus erythematosus, 6 with rheumatoid arthritis, 4 with overlap syndrome, 2 with Sjögren syndrome, and 2 with inflammatory arthritis), 49 matched patients without RP or AIRD (78% female; 64 ± 13 yrs), and 14 healthy participants (50% female; 35 ± 5 yrs) were studied. Patients with primary RP, matched patient controls, and healthy participants had comparable MFR. Patients with SSc-RP had significantly reduced MFR (1.62 ± 0.32) compared to matched patient controls ( P = 0.03, 2.06 ± 0.61) and to healthy participants ( P = 0.01, 2.22 ± 0.44). In multivariable logistic regression, SSc was an independent predictor of reduced MFR. We identified a correlation between time since AIRD diagnosis and MFR (r = -0.30, 95% CI -0.63 to -0.02, P = 0.04)., Conclusion: Our findings suggest that only secondary, not primary, RP is associated with reduced MFR, and that patients with SSc-RP have reduced MFR compared to those with primary RP and patients with other AIRDs. Larger prospective studies are warranted to fully elucidate the prognostic value of MFR in patients with secondary RP., (Copyright © 2021 by the Journal of Rheumatology.)

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/1.73m 2 ). 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/1.73m 2 ), 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/1.73m 2 (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/1.73m 2 ) 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.

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., (© 2020 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Introduction: Uncontrolled type 2 diabetes (T2D) is associated with an increased risk of micro- and macrovascular complications and mortality. The impact of basal insulins on the risks of mortality and cardiovascular mortality in people with T2D has not been thoroughly investigated in real-world settings. The aim of the present real-word study was to investigate differences in mortality among insulin-naïve people with T2D who initiated insulin detemir (detemir) and insulin glargine (glargine)., Methods: We assessed all-cause and cardiovascular mortality in people with T2D, aged ≥ 40 years and insulin-naïve at treatment initiation. People were identified from the United Kingdom Clinical Practice Research Datalink GOLD national database (2004-2019). Database information included prescribed medications, demographic and clinical variables and mortality. Cause of death was obtained from the Office for National Statistics (ONS). For mortality, 24 clinically relevant confounders were considered and adjusted for using Cox regression analyses., Results: The total cohort included 12,847 people with T2D, including 3031 who commenced detemir and 9816 who commenced glargine. Median age was 66.8 years and median diabetes duration was 7.6 years. From the total cohort, 3231 deaths occurred during follow-up and 6897 people were eligible for linkage to the ONS for cardiovascular mortality data (528 cardiovascular deaths). The adjusted hazard ratio (HR) (95% confidence interval [CI]) was 0.86 (0.79; 0.95) for all-cause mortality and 0.83 (0.67; 1.03) for cardiovascular mortality, in favour of detemir versus glargine. These associations were more pronounced among people with obesity (body mass index ≥ 30 kg/m 2 ), with HRs (95% CI) of 0.79 (0.69; 0.91) and 0.69 (0.50; 0.96) for all-cause and cardiovascular mortality, respectively., Conclusion: In this real-world observational study, there was an association between all-cause mortality and basal insulin choice in insulin-naïve people with T2D; the mortality risk was lower with detemir versus glargine after adjustment for potential confounders.

Hypertension has been identified as a risk factor for coronavirus disease 2019 (COVID-19) and associated adverse outcomes. This study examined the association between preinfection blood pressure (BP) control and COVID-19 outcomes using data from 460 general practices in England. Eligible patients were adults with hypertension who were tested or diagnosed with COVID-19. BP control was defined by the most recent BP reading within 24 months of the index date (January 1, 2020). BP was defined as controlled (<130/80 mm Hg), raised (130/80-139/89 mm Hg), stage 1 uncontrolled (140/90-159/99 mm Hg), or stage 2 uncontrolled (≥160/100 mm Hg). The primary outcome was death within 28 days of COVID-19 diagnosis. Secondary outcomes were COVID-19 diagnosis and COVID-19-related hospital admission. Multivariable logistic regression was used to examine the association between BP control and outcomes. Of the 45 418 patients (mean age, 67 years; 44.7% male) included, 11 950 (26.3%) had controlled BP. These patients were older, had more comorbidities, and had been diagnosed with hypertension for longer. A total of 4277 patients (9.4%) were diagnosed with COVID-19 and 877 died within 28 days. Individuals with stage 1 uncontrolled BP had lower odds of COVID-19 death (odds ratio, 0.76 [95% CI, 0.62-0.92]) compared with patients with well-controlled BP. There was no association between BP control and COVID-19 diagnosis or hospitalization. These findings suggest BP control may be associated with worse COVID-19 outcomes, possibly due to these patients having more advanced atherosclerosis and target organ damage. Such patients may need to consider adhering to stricter social distancing, to limit the impact of COVID-19 as future waves of the pandemic occur.

Increasing evidence points to endothelial cell dysfunction as a key pathophysiological factor in severe coronavirus disease-19 (COVID-19), manifested by platelet aggregation, microthrombi and altered vasomotor tone. This may be driven by direct endothelial cell entry by the virus, or indirectly by activated inflammatory cascade. Major risk groups identified for adverse outcomes in COVID-19 are diabetes, and those from the Black, Asian and ethnic minority (BAME) populations. Hyperglycaemia (expressed as glycated haemoglobin or mean hospital glucose) correlates with worse outcomes in COVID-19. It is not known whether hyperglycaemia is causative or is a surrogate marker - persistent hyperglycaemia is well known as an aetiological agent in microangiopathy. In this article, we propose that pre-existing endothelial dysfunction of microangiopathy, more commonly evident in diabetes and BAME groups, makes an individual vulnerable to the subsequent 'endothelitis' of COVID-19 infection., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are oral antihyperglycemic agents for the treatment of people with type 2 diabetes (T2DM). Two recent cardiovascular outcome trials (CVOTs), the EMPA-REG OUTCOME trial and CANVAS Program, have demonstrated that SGLT2 inhibitors have cardiovascular benefit in high-risk cardiovascular patients. The aim of our study will be to identify the prevalence of patients in an English primary care setting with the equivalent cardiovascular risk profile to those included in each of four SGLT2 inhibitor CVOTs: CANVAS, DECLARE, EMPA-REG, and VERTIS CV., Methods: Routinely collected primary care data from the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network database will be used. We will perform a cross-sectional analysis to calculate the prevalence of people that have equivalent cardiovascular risk to participants included in each of the four above-mentioned SGLT2 inhibitor CVOTs. The demographic and clinical characteristics of the subgroups will also be compared with participants in each trial. The study cohort will include people with T2DM in the RCGP RSC dataset. Subgroups of people will be identified using Read codes that most closely match the inclusion criteria of each trial. Descriptive statistics will be used to report the characteristics of people at high cardiovascular risk and compared against those of people in each CVOT., Planned Outputs: Findings from the study will be submitted for publication in a peer-reviewed journal to report the applicability of each SGLT2 inhibitor trial to real-world clinical practice., Funding: AstraZeneca UK Limited.

Background: Gout is a painful disorder and is common in type 2 diabetes. Fenofibrate lowers uric acid and reduces gout attacks in small, short-term studies. Whether fenofibrate produces sustained reductions in uric acid and gout attacks is unknown., Methods: In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, participants aged 50-75 years with type 2 diabetes were randomly assigned to receive either co-micronised fenofibrate 200 mg once per day or matching placebo for a median of 5 years follow-up. We did a post-hoc analysis of recorded on-study gout attacks and plasma uric acid concentrations according to treatment allocation. The outcomes of this analysis were change in uric acid concentrations and risk of on-study gout attacks. The FIELD study is registered with ISRCTN, number ISRCTN64783481., Findings: Between Feb 23, 1998, and Nov 3, 2000, 9795 patients were randomly assigned to fenofibrate (n=4895) or placebo (n=4900) in the FIELD study. Uric acid concentrations fell by 20·2% (95% CI 19·9-20·5) during the 6-week active fenofibrate run-in period immediately pre-randomisation (a reduction of 0·06 mmol/L or 1 mg/dL) and remained -20·1% (18·5-21·7, p<0·0001) lower in patients taking fenofibrate than in those on placebo in a random subset re-measured at 1 year. With placebo allocation, there were 151 (3%) first gout events over 5 years, compared with 81 (2%) among those allocated fenofibrate (HR with treatment 0·54, 95% CI 0·41-0·70; p<0·0001). In the placebo group, the cumulative proportion of patients with first gout events was 7·7% in patients with baseline uric acid concentration higher than 0·36 mmol/L and 13·9% in those with baseline uric acid concentration higher than 0·42 mmol/L, compared with 3·4% and 5·7%, respectively, in the fenofibrate group. Risk reductions were similar among men and women and those with dyslipidaemia, on diuretics, and with elevated uric acid concentrations. For participants with elevated baseline uric acid concentrations despite taking allopurinol at study entry, there was no heterogeneity of the treatment effect of fenofibrate on gout risk. Taking account of all gout events, fenofibrate treatment halved the risk (HR 0·48, 95% CI 0·37-0·60; p<0·0001) compared with placebo., Interpretation: Fenofibrate lowered uric acid concentrations by 20%, and almost halved first on-study gout events over 5 years of treatment. Fenofibrate could be a useful adjunct for preventing gout in diabetes., Funding: None., (Copyright © 2018 Elsevier Ltd. All rights reserved.)