Recent Submissions

  • Translating trial results into interpretable risk estimates: Systematic analysis of cardiorenal outcome trials of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors Authors

    Davies, Melanie J; Zaccardi, Francesco (2023-12-20)
    Background and aims: In a randomised controlled trial (RCT), the between-arm difference in the average probability of an event per unit of time (i.e., yearly incidence risk difference, YIRD) is an easy-to-interpret treatment effect metric. We aimed to quantify the YIRD in cardiorenal RCTs of GLP-1RAs or SGLT-2is. Methods and results: We digitally searched for RCTs published up to March 1st, 2023, including subjects with type 2 diabetes randomised to GLP-1RAs or SGLT-2is and investigating cardiorenal outcomes or death. We extracted information from Kaplan-Meier (KM) plots to obtain time-to-event individual data and estimate within-arm yearly incidence risk and YIRD. Data from 19 RCTs (28 kM plots) were analysed: comparing treatment to placebo, in GLP-1RA RCTs the YIRD ranged from 0.2 % (95 % CI: -0.7 %, 1.1 %) to -1.9 % (-3.1, -0.7), for primary outcome; and from -0.2 % (-0.5, 0.2) to -0.4 % (-0.7 %, -0.0 %), for mortality. With the exception of SOLOIST-WHF (YIRD 11.9 % for primary outcome), corresponding estimates in SGLT-2is RCTs were: from -0.1 % (-0.4, 0.1) to -5.0 % (-7.7, -2.6), for primary outcome; and from -0.1 % (-0.2, 0.1) to -1.9 % (-4.4 %, 0.6 %), for mortality. Conclusion: The YIRD metric complements other relative treatment effect estimates and helps quantify the absolute benefit of GLP-1RAs and SGLT-2is.
  • Improving self-management behaviour through a digital lifestyle intervention: An internal pilot study

    Davies, Melanie; Graham-Brown, Matthew P M; Lightfoot, Courtney; Vadaszy, Noemi (2024-01-31)
    Background: Self-management is a key component of successful chronic kidney disease (CKD) management. Here, we present the findings from the internal pilot of a multicentre randomised controlled trial (RCT) aimed to test the effect of a digital self-management programme ('My Kidneys & Me' (MK&M)). Methods: Participants (aged ≥18 years and CKD stages 3-4) were recruited from hospital kidney services across England. Study processes were completed virtually. Participants were randomised 2:1 to either intervention (MK&M) or control group. The first 60 participants recruited were included in a 10-week internal pilot which assessed study feasibility and acceptability against pre-specified progression criteria: 1) eligibility and recruitment, acceptability of 2) randomisation and 3) outcomes, 4) MK&M activation, and 5) retention and attrition rates. Semi-structured interviews further explored views on trial participation. Results: Of the 60 participants recruited, 41 were randomised to MK&M and 19 to control. All participants completed baseline measures and 62% (n=37) completed post-intervention outcome measures. All progression criteria met the minimum thresholds to proceed. Nine participants were interviewed. The themes identified were satisfaction with study recruitment processes (openness to participate, reading and agreeing to "terms and conditions"), acceptability of study design (remote study participation, acceptability of randomisation, completion of online assessment(s)), and methods to improve recruitment and retention (personalised approach, follow-up communication). Conclusion: This internal pilot demonstrated the feasibility and acceptability of a virtually run RCT. Progression criteria thresholds to proceed to the definitive RCT were met. Areas for improvement were identified and protocol amendments were made to improve trial delivery.
  • Impact of weight loss and weight gain trajectories on body composition in a population at high risk of type 2 diabetes: a prospective cohort analysis

    Arsenyadis, F; Biddle, G J H; Davies, M J; Henson, J; Papamargaritis, D; Webb, David R (2024-03)
    Aim: In a primary care population at high risk of type 2 diabetes, 24-month weight change trajectories were used to investigate the impact of weight cycling on fat mass (FM) and fat-free mass (FFM). Materials and methods: Cohort data from the Walking Away from Type 2 Diabetes trial was used, which recruited adults at-risk of type 2 diabetes from primary care in 2009/10. Annual weight change trajectories based on weight loss/gain of ≥5% were assessed over two 24-month periods. Body composition was measured by bioelectrical impedance analysis. Repeated measures were analysed using generalized estimating equations with participants contributing up to two 24-month observation periods. Results: In total, 622 participants were included (average age = 63.6 years, body mass index = 32.0 kg/m2 , 35.4% women), contributing 1163 observations. Most observations (69.2%) were from those that maintained their body weight, with no change to FM or FFM. A minority (4.6% of observations) lost over 5% of body weight between baseline and 12 months, which was then regained between 12 and 24 months. These individuals regained FM to baseline levels, but lost 1.50 (0.66, 2.35) kg FFM, adjusted for confounders. In contrast, those that gained weight between baseline and 12 months but lost weight between 12 and 24 months (5.5% of observations) had a net gain in FM of 1.70 (0.27, 3.12) kg with no change to FFM. Conclusion: Weight cycling may be associated with a progressive loss in FFM and/or gain in FM in those with overweight and obesity at-risk of type 2 diabetes.
  • What is the pipeline for future medications for obesity?

    Davies, Melanie J; Melson, Eka; Papamargaritis, Dimitris; Uzma, Ashraf (2024-02-01)
    Obesity is a chronic disease associated with increased risk of obesity-related complications and mortality. Our better understanding of the weight regulation mechanisms and the role of gut-brain axis on appetite has led to the development of safe and effective entero-pancreatic hormone-based treatments for obesity such as glucagon-like peptide-1 (GLP-1) receptor agonists (RA). Semaglutide 2.4 mg once weekly, a subcutaneously administered GLP-1 RA approved for obesity treatment in 2021, results in 15-17% mean weight loss (WL) with evidence of cardioprotection. Oral GLP-1 RA are also under development and early data shows similar WL efficacy to semaglutide 2.4 mg. Looking to the next generation of obesity treatments, combinations of GLP-1 with other entero-pancreatic hormones with complementary actions and/or synergistic potential (such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) are under investigation to enhance the WL and cardiometabolic benefits of GLP-1 RA. Tirzepatide, a dual GLP-1/GIP receptor agonist has been approved for glycaemic control in type 2 diabetes as well as for obesity management leading in up to 22.5% WL in phase 3 obesity trials. Other combinations of entero-pancreatic hormones including cagrisema (GLP-1/amylin RA) and the triple agonist retatrutide (GLP-1/GIP/glucagon RA) have also progressed to phase 3 trials as obesity treatments and early data suggests that may lead to even greater WL than tirzepatide. Additionally, agents with different mechanisms of action to entero-pancreatic hormones (e.g. bimagrumab) may improve the body composition during WL and are in early phase clinical trials. We are in a new era for obesity pharmacotherapy where combinations of entero-pancreatic hormones approach the WL achieved with bariatric surgery. In this review, we present the efficacy and safety data for the pipeline of obesity pharmacotherapies with a focus on entero-pancreatic hormone-based treatments and we consider the clinical implications and challenges that the new era in obesity management may bring.
  • Ethnic differences in cardiac structure and function assessed by MRI in healthy South Asian and White European people: a UK Biobank Study

    Alfuhied, Aseel; Arnold, Jayanth; Ayton, Sarah; Bilak, Joanna; Brady, Emer M; Dattani, Abhishek; Gulsin, Gaurav; Graham-Brown, Matthew P; McCann, Gerry P; SIngh, Anvesha; et al.
    Background: Echocardiographic studies indicate South Asian people have smaller ventricular volumes, lower mass and more concentric remodelling than White European people, but there are no data using cardiac MRI (CMR). We aimed to compare CMR quantified cardiac structure and function in White European and South Asian people. Methods: Healthy White European and South Asian participants in the UK Biobank Imaging CMR sub-study were identified by excluding those with a history of cardiovascular disease, hypertension, obesity or diabetes. Ethnic groups were matched by age and sex. Cardiac volumes, mass and feature tracking strain were compared. Results: 121 matched pairs (77 male/44 female, mean age 58±8 years) of South Asian and White European participants were included. South Asian males and females had smaller absolute but not indexed left ventricular (LV) volumes, and smaller absolute and indexed right ventricular volumes, with lower absolute and indexed LV mass and lower LV mass:volume than White European participants. Although there were no differences in ventricular or atrial ejection fractions, LV global longitudinal strain was higher in South Asian females than White European females but not males, and global circumferential strain was higher in both male and South Asian females than White European females. Peak early diastolic strain rates were higher in South Asian versus White European males, but not different between South Asian and White European females. Conclusions: Contrary to echocardiographic studies, South Asian participants in the UK Biobank study had less concentric remodelling and higher global circumferential strain than White European subjects. These findings emphasise the importance of sex- and ethnic- specific normal ranges for cardiac volumes and function.
  • Real-world study of the concomitant use of biphasic insulin as part 30/70 with GLP-1 receptor agonist versus first-generation basal insulin with GLP-1 receptor agonist in type 2 diabetes

    Davies, Melanie J (2023-12-13)
    Aims: Combining insulin with a glucagon-like peptide-1 receptor agonist (GLP-1RA) to treat type 2 diabetes (T2D) is common. While many studies have investigated concomitant therapy with basal insulin+GLP-1RA, few have reported on premixed insulin+GLP-1RA. We aimed to address this gap using data from the Clinical Practice Research Datalink Aurum database in England. Methods: This retrospective cohort study with propensity score matching assessed glycaemic levels and other clinical outcomes in people with T2D, comparing biphasic insulin aspart 30/70 (BIAsp 30) + GLP-1RA with basal insulin (insulin detemir/glargine U100) + GLP-1RA (from 2006 to 2021). Results: In total, 4770 eligible people were identified; 1511 had a BIAsp 30 + GLP-1RA regimen and were propensity score-matched to an equal number receiving basal+GLP-1RA. There was no significant difference in glycated haemoglobin (HbA1c) reduction between cohorts at 6 months (p = 0.15), with a decrease of -1.07 (95% CI: -1.16; -0.98) %-points (-11.7 mmol/mol [95% CI: -12.7; -10.7]) in the BIAsp 30 + GLP-1RA cohort, versus -0.97 (95% CI: -1.07; -0.88) %-points (-10.6 mmol/mol [95% CI: -11.7; -9.6]) in the basal+GLP-1RA cohort. Body mass index (BMI) decreased by -0.35 kg/m2 (95% CI: -0.52;-0.18) at 6 months with BIAsp 30 + GLP-1RA, versus -0.72 kg/m2 (95% CI: -0.90;-0.54) with basal+GLP-1RA (p = 0.003). BMI was influenced by the initiation sequence of GLP-1RA in relation to insulin (p < 0.0001). Hypoglycaemia rates were low and not significantly different between cohorts. Conclusions: Combining BIAsp 30 + GLP-1RA provides glycaemic control with no significant difference to that of propensity score-matched people receiving basal insulin+GLP-1RA, with no increase in hypoglycaemia risk or weight gain.
  • Implementation and engagement of the SMART Work & Life sitting reduction intervention: an exploratory analysis on intervention effectiveness

    Wilson, Panna (2023-12-19)
    Background: To enhance the impact of interventions, it is important to understand how intervention engagement relates to study outcomes. We report on the level of implementation and engagement with the SMART Work & Life (SWAL) programme (delivered with (SWAL plus desk) and without a height-adjustable desk (SWAL)) and explore the effects of different levels of this on change in daily sitting time in comparison to the control group. Methods: The extent of intervention delivery by workplace champions and the extent of engagement by champions and participants (staff) with each intervention activity was assessed by training attendance logs, workplace champion withdrawal dates, intervention activities logs and questionnaires. These data were used to assess whether a cluster met defined criteria for low, medium, or high implementation and engagement or none of these. Mixed effects linear regression analyses tested whether change in sitting time varied by: (i) the number of intervention activities implemented and engaged with, and (ii) the percentage of implementation and engagement with all intervention strategies. Results: Workplace champions were recruited for all clusters, with 51/52 (98%) attending training. Overall, 12/27 (44.4%) SWAL and 9/25 (36.0%) SWAL plus desk clusters implemented all main intervention strategies. Across remaining clusters, the level of intervention implementation varied. Those in the SWAL (n = 8 (29.6%) clusters, 80 (32.1%) participants) and SWAL plus desk (n = 5 (20.0%) clusters, 41 (17.1%) participants) intervention groups who implemented and engaged with the most intervention strategies and had the highest percentage of cluster implementation and engagement with all intervention strategies sat for 30.9 (95% CI -53.9 to -7.9, p = 0.01) and 75.6 (95% CI -103.6 to -47.7, p < 0.001) fewer minutes/day respectively compared to the control group at 12 month follow up. These differences were larger than the complete case analysis. The differences in sitting time observed for the medium and low levels were similar to the complete case analysis. Conclusions: Most intervention strategies were delivered to some extent across the clusters although there was large variation. Superior effects for sitting reduction were seen for those intervention groups who implemented and engaged with the most intervention components and had the highest level of cluster implementation and engagement. Trial registration: ISRCTN11618007. Registered on 24 January 2018. .
  • Twenty-four-hour physical behaviour profiles across type 2 diabetes mellitus subtypes

    Davies, Melanie J; Hall, Andrew P; Henson, Joseph (2024-01-08)
    Aim: To investigate how 24-h physical behaviours differ across type 2 diabetes (T2DM) subtypes. Materials and methods: We included participants living with T2DM, enrolled as part of an ongoing observational study. Participants wore an accelerometer for 7 days to quantify physical behaviours across 24 h. We used routinely collected clinical data (age at onset of diabetes, glycated haemoglobin level, homeostatic model assessment index of beta-cell function, homeostatic model assessment index of insulin resistance, body mass index) to replicate four previously identified subtypes (insulin-deficient diabetes [INS-D], insulin-resistant diabetes [INS-R], obesity-related diabetes [OB] and age-related diabetes [AGE]), via k-means clustering. Differences in physical behaviours across the diabetes subtypes were assessed using generalized linear models, with the AGE cluster as the reference. Results: A total of 564 participants were included in this analysis (mean age 63.6 ± 8.4 years, 37.6% female, mean age at diagnosis 53.1 ± 10.0 years). The proportions in each cluster were as follows: INS-D: n = 35, 6.2%; INS-R: n = 88, 15.6%; OB: n = 166, 29.4%; and AGE: n = 275, 48.8%. Compared to the AGE cluster, the OB cluster had a shorter sleep duration (-0.3 h; 95% confidence interval [CI] -0.5, -0.1), lower sleep efficiency (-2%; 95% CI -3, -1), lower total physical activity (-2.9 mg; 95% CI -4.3, -1.6) and less time in moderate-to-vigorous physical activity (-6.6 min; 95% CI -11.4, -1.7), alongside greater sleep variability (17.9 min; 95% CI 8.2, 27.7) and longer sedentary time (31.9 min; 95% CI 10.5, 53.2). Movement intensity during the most active continuous 10 and 30 min of the day was also lower in the OB cluster. Conclusions: In individuals living with T2DM, the OB subtype had the lowest levels of physical activity and least favourable sleep profiles. Such behaviours may be suitable targets for personalized therapeutic lifestyle interventions.
  • The development and internal pilot trial of a digital physical activity and emotional well-being intervention (Kidney BEAM) for people with chronic kidney disease

    Billany, Roseanne; Burton, James O; Graham-Brown, Matthew; Young, Hannah (2024-01-06)
    This trial assessed the feasibility and acceptability of Kidney BEAM, a physical activity and emotional well-being self-management digital health intervention (DHI) for people with chronic kidney disease (CKD), which offers live and on-demand physical activity sessions, educational blogs and videos, and peer support. In this mixed-methods, multicentre randomised waitlist-controlled internal pilot, adults with established CKD were recruited from five NHS hospitals and randomised 1:1 to Kidney BEAM or waitlist control. Feasibility outcomes were based upon a priori progression criteria. Acceptability was primarily explored via individual semi-structured interviews (n = 15). Of 763 individuals screened, n = 519 (68%, 95% CI 65 to 71%) were eligible. Of those eligible, n = 303 (58%, 95% CI 54-63%) did not respond to an invitation to participate by the end of the pilot period. Of the 216 responders, 50 (23%, 95% CI 18-29%) consented. Of the 42 randomised, n = 22 (10 (45%) male; 49 ± 16 years; 14 (64%) White British) were allocated to Kidney BEAM and n = 20 (12 (55%) male; 56 ± 11 years; 15 (68%) White British) to the waitlist control group. Overall, n = 15 (30%, 95% CI 18-45%) withdrew during the pilot phase. Participants completed a median of 14 (IQR 5-21) sessions. At baseline, 90-100% of outcome data (patient reported outcome measures and a remotely conducted physical function test) were completed and 62-83% completed at 12 weeks follow-up. Interview data revealed that remote trial procedures were acceptable. Participants' reported that Kidney BEAM increased their opportunity and motivation to be physically active, however, lack of time remained an ongoing barrier to engagement with the DHI. An randomised controlled trial of Kidney BEAM is feasible and acceptable, with adaptations to increase recruitment, retention and engagement.Trial registration NCT04872933. Date of first registration 05/05/2021.
  • Circulating sphingolipids and relationship to cardiac remodelling before and following a low-energy diet in asymptomatic Type 2 Diabetes

    Athithan, Lavanya; Ayton, Sarah; Brady, Emer; Davies, Melanie J; Graham-Brown, Matthew; Gulsin, Gaurav; McCann, Gerry; Moss, Esther; Redman, Emma (2024-01-03)
    Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogenous multi-system syndrome with limited efficacious treatment options. The prevalence of Type 2 diabetes (T2D) continues to rise and predisposes patients to HFpEF, and HFpEF remains one of the biggest challenges in cardiovascular medicine today. Novel therapeutic targets are required to meet this important clinical need. Deep phenotyping studies including -OMIC analyses can provide important pathogenic information to aid the identification of such targets. The aims of this study were to determine; 1) the impact of a low-energy diet on plasma sphingolipid/ceramide profiles in people with T2D compared to healthy controls and, 2) if the change in sphingolipid/ceramide profile is associated with reverse cardiovascular remodelling. Methods: Post-hoc analysis of a randomised controlled trial (NCT02590822) including adults with T2D with no cardiovascular disease who completed a 12-week low-energy (∼810 kcal/day) meal-replacement plan (MRP) and matched healthy controls (HC). Echocardiography, cardiac MRI and a fasting blood for lipidomics were undertaken pre/post-intervention. Candidate biomarkers were identified from case-control comparison (fold change > 1.5 and statistical significance p < 0.05) and their response to the MRP reported. Association between change in biomarkers and change indices of cardiac remodelling were explored. Results: Twenty-four people with T2D (15 males, age 51.1 ± 5.7 years), and 25 HC (15 male, 48.3 ± 6.6 years) were included. Subjects with T2D had increased left ventricular (LV) mass:volume ratio (0.84 ± 0.13 vs. 0.70 ± 0.08, p < 0.001), increased systolic function but impaired diastolic function compared to HC. Twelve long-chain polyunsaturated sphingolipids, including four ceramides, were downregulated in subjects with T2D at baseline. Three sphingomyelin species and all ceramides were inversely associated with LV mass:volume. There was a significant increase in all species and shift towards HC following the MRP, however, none of these changes were associated with reverse cardiac remodelling. Conclusion: The lack of association between change in sphingolipids/ceramides and reverse cardiac remodelling following the MRP casts doubt on a causative role of sphingolipids/ceramides in the progression of heart failure in T2D.
  • Association between ethnicity and migration status with the prevalence of single and multiple long-term conditions in UK healthcare worker

    Ekezie, Winifred; Martin, Christopher A; Nazareth, Joshua; Pan, Daniel; Pareek, Manish; Sze, Shirley (2023-11-30)
    Background: Healthcare workers' (HCW) well-being has a direct effect on patient care. However, little is known about the prevalence and patterns of long-term medical conditions in HCWs, especially those from ethnic minorities. This study evaluated the burden of multiple long-term conditions (MLTCs), i.e. the presence of two or more single long-term conditions (LTCs), among HCWs in the United Kingdom (UK) and variation by ethnicity and migration status. Methods: We used baseline data from the UK-REACH cohort study collected December 2020-March 2021. We used multivariable logistic regression, adjusting for demographic, occupational and lifestyle factors to examine the relationship between self-reported LTCs/MLTCs and ethnicity, migration status and time since migration to the UK. Results: Of 12,100 included HCWs, with a median age of 45 years (IQR: 34-54), 27% were overseas-born, and 30% were from non-White ethnic groups (19% Asian, 4% Black, 4% Mixed, 2% Other). The most common self-reported LTCs were anxiety (14.9%), asthma (12.2%), depression (10.7%), hypertension (8.7%) and diabetes (4.0%). Mental health conditions were more prevalent among UK-born than overseas-born HCWs for all ethnic groups (adjusted odds ratio (aOR) using White UK-born as the reference group each time: White overseas-born 0.77, 95%CI 0.66-0.95 for anxiety). Diabetes and hypertension were more common among Asian (e.g. Asian overseas, diabetes aOR 2.97, 95%CI 2.30-3.83) and Black (e.g. Black UK-born, hypertension aOR 1.77, 95%CI 1.05-2.99) groups than White UK-born. After adjustment for age, sex and deprivation, the odds of reporting MLTCs were lower in most ethnic minority groups and lowest for those born overseas, compared to White UK-born (e.g. White overseas-born, aOR 0.68, 95%CI 0.55-0.83; Asian overseas-born aOR 0.75, 95%CI 0.62-0.90; Black overseas-born aOR 0.52, 95%CI 0.36-0.74). The odds of MLTCs in overseas-born HCWs were equivalent to the UK-born population in those who had settled in the UK for ≥ 20 years (aOR 1.14, 95%CI 0.94-1.37). Conclusions: Among UK HCWs, the prevalence of common LTCs and odds of reporting MLTCs varied by ethnicity and migrant status. The lower odds of MLTCs in migrant HCWs reverted to the odds of MLTCs in UK-born HCWs over time. Further research on this population should include longitudinal studies with linkage to healthcare records. Interventions should be co-developed with HCWs from different ethnic and migrant groups focussed upon patterns of conditions prevalent in specific HCW subgroups to reduce the overall burden of LTCs/MLTCs.
  • Impact of weight loss and weight gain trajectories on body composition in a population at high risk of type 2 diabetes:a prospective cohort analysis

    Arsenyadis, F; Biddle, G; Davies, M J; Papamargaritis, D; Webb, D (2023-12-14)
    Aim: In a primary care population at high risk of type 2 diabetes, 24-month weight change trajectories were used to investigate the impact of weight cycling on fat mass (FM) and fat-free mass (FFM). Materials and methods: Cohort data from the Walking Away from Type 2 Diabetes trial was used, which recruited adults at-risk of type 2 diabetes from primary care in 2009/10. Annual weight change trajectories based on weight loss/gain of ≥5% were assessed over two 24-month periods. Body composition was measured by bioelectrical impedance analysis. Repeated measures were analysed using generalized estimating equations with participants contributing up to two 24-month observation periods. Results: In total, 622 participants were included (average age = 63.6 years, body mass index = 32.0 kg/m2 , 35.4% women), contributing 1163 observations. Most observations (69.2%) were from those that maintained their body weight, with no change to FM or FFM. A minority (4.6% of observations) lost over 5% of body weight between baseline and 12 months, which was then regained between 12 and 24 months. These individuals regained FM to baseline levels, but lost 1.50 (0.66, 2.35) kg FFM, adjusted for confounders. In contrast, those that gained weight between baseline and 12 months but lost weight between 12 and 24 months (5.5% of observations) had a net gain in FM of 1.70 (0.27, 3.12) kg with no change to FFM. Conclusion: Weight cycling may be associated with a progressive loss in FFM and/or gain in FM in those with overweight and obesity at-risk of type 2 diabetes.
  • Efficacy and Safety of Continuous Glucose Monitoring and Intermittently Scanned Continuous Glucose Monitoring in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis of Interventional Evidence

    Choudhary, Pratik (2024-01-01)
    Background: Traditional diabetes self-monitoring of blood glucose (SMBG) involves inconvenient finger pricks. Continuous glucose monitoring (CGM) and intermittently scanned CGM (isCGM) systems offer CGM, enhancing type 2 diabetes (T2D) management with convenient, comprehensive data. Purpose: To assess the benefits and potential harms of CGM and isCGM compared with usual care or SMBG in individuals with T2D. Data sources: We conducted a comprehensive search of MEDLINE, Embase, the Cochrane Library, Web of Science, and bibliographies up to August 2023. Study selection: We analyzed studies meeting these criteria: randomized controlled trials (RCT) with comparison of at least two interventions for ≥8 weeks in T2D patients, including CGM in real-time/retrospective mode, short-/long-term CGM, isCGM, and SMBG, reporting glycemic and relevant data. Data extraction: We used a standardized data collection form, extracting details including author, year, study design, baseline characteristics, intervention, and outcomes. Data synthesis: We included 26 RCTs (17 CGM and 9 isCGM) involving 2,783 patients with T2D (CGM 632 vs. usual care/SMBG 514 and isCGM 871 vs. usual care/SMBG 766). CGM reduced HbA1c (mean difference -0.19% [95% CI -0.34, -0.04]) and glycemic medication effect score (-0.67 [-1.20 to -0.13]), reduced user satisfaction (-0.54 [-0.98, -0.11]), and increased the risk of adverse events (relative risk [RR] 1.22 [95% CI 1.01, 1.47]). isCGM reduced HbA1c by -0.31% (-0.46, -0.17), increased user satisfaction (0.44 [0.29, 0.59]), improved CGM metrics, and increased the risk of adverse events (RR 1.30 [0.05, 1.62]). Neither CGM nor isCGM had a significant impact on body composition, blood pressure, or lipid levels. Limitations: Limitations include small samples, single-study outcomes, population variations, and uncertainty for younger adults. Additionally, inclusion of <10 studies for most end points restricted comprehensive analysis, and technological advancements over time need to be considered. Conclusions: Both CGM and isCGM demonstrated a reduction in HbA1c levels in individuals with T2D, and unlike CGM, isCGM use was associated with improved user satisfaction. The impact of these devices on body composition, blood pressure, and lipid levels remains unclear, while both CGM and isCGM use were associated with increased risk of adverse events.
  • Clinicians' interpretation of unreported chest radiographs in biologic prescription workup service: a comprehensive analysis

    Farman, Fatima; Murad, Awin Mohammed; Sunmboye, Kehinde (2023-11-15)
    Clinicians without a radiology specialization face difficulties when they attempt to interpret chest X-rays (CXRs), a crucial and extensively utilized diagnostic tool that plays a fundamental role in the detection of pulmonary and cardiovascular disorders. This cross-sectional study assessed the confidence and competence of clinicians, including junior specialty trainees, higher specialty trainees, and specialist nurses, in interpreting CXRs before starting biological treatment. An online survey was used to collect data from clinicians in various healthcare settings, focusing on their experience, training, confidence levels, and CXR interpretation proficiency. The survey uncovered clinicians' insufficient confidence in interpreting the pre-biological screening CXRs despite their clinical expertise. This uncertainty raises concerns about potential misinterpretations, affecting timely treatment decisions. A Kruskal-Wallis test indicated a significant difference between training levels required with a p-value of 0.001, rejecting the null hypothesis. Subsequently, a Dunn-Bonferroni test revealed that the higher specialty trainee-specialist nurse pair differed significantly, with the specialist nurse group requiring more training. This study highlighted the need for enhanced radiology education for clinicians involved in chest radiograph interpretation for pre-biological screening. Implementing a structured training program is essential to improve skills and ensure accurate interpretation of non-formally reported chest radiographs, ultimately enhancing patient outcomes and healthcare practices.
  • Long-term ambient air pollution exposure and prospective change in sedentary behaviour and physical activity in individuals at risk of type 2 diabetes in the UK

    Davies, Melanie J; Henson, Joseph; Goldney, Jonathan (2023-12-16)
    Background: Air pollution may be a risk factor for physical inactivity and sedentary behaviour (SED) through discouraging active lifestyles, impairing fitness and contributing to chronic diseases with potentially important consequences for population health. Methods: Using generalized estimating equations, we examined the associations between long-term particulate matter with diameter ≤2.5 μm (PM2.5), ≤10 μm (PM10) and nitrogen dioxide (NO2) and annual change in accelerometer-measured SED, moderate-to-vigorous physical activity (MVPA) and steps in adults at risk of type 2 diabetes within the Walking Away from Type 2 Diabetes trial. We adjusted for important confounders including social deprivation and measures of the built environment. Results: From 808 participants, 644 had complete data (1605 observations; 64.7% men; mean age 63.86 years). PM2.5, NO2 and PM10 were not associated with change in MVPA/steps but were associated with change in SED, with a 1 ugm-3 increase associated with 6.38 (95% confidence interval: 0.77, 12.00), 1.52 (0.49, 2.54) and 4.48 (0.63, 8.34) adjusted annual change in daily minutes, respectively. Conclusions: Long-term PM2.5, NO2 and PM10 exposures were associated with an annual increase in SED: ~11-22 min/day per year across the sample range of exposure (three standard deviations). Future research should investigate whether interventions to reduce pollution may influence SED.
  • Resource efficient aortic distensibility calculation by end to end spatiotemporal learning of aortic lumen from multicentre multivendor multidisease CMR images

    Adlam, David; Davies, Melanie J; Graham-Brown, Matthew P M; McCann, Gerry P; Meisuria, Mitul; Singh, Anvesha; Wormleighton, Joanne (2023-12-08)
    Aortic distensibility (AD) is important for the prognosis of multiple cardiovascular diseases. We propose a novel resource-efficient deep learning (DL) model, inspired by the bi-directional ConvLSTM U-Net with densely connected convolutions, to perform end-to-end hierarchical learning of the aorta from cine cardiovascular MRI towards streamlining AD quantification. Unlike current DL aortic segmentation approaches, our pipeline: (i) performs simultaneous spatio-temporal learning of the video input, (ii) combines the feature maps from the encoder and decoder using non-linear functions, and (iii) takes into account the high class imbalance. By using multi-centre multi-vendor data from a highly heterogeneous patient cohort, we demonstrate that the proposed method outperforms the state-of-the-art method in terms of accuracy and at the same time it consumes [Formula: see text] 3.9 times less fuel and generates [Formula: see text] 2.8 less carbon emissions. Our model could provide a valuable tool for exploring genome-wide associations of the AD with the cognitive performance in large-scale biomedical databases. By making energy usage and carbon emissions explicit, the presented work aligns with efforts to keep DL's energy requirements and carbon cost in check. The improved resource efficiency of our pipeline might open up the more systematic DL-powered evaluation of the MRI-derived aortic stiffness.
  • Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial

    Davies, Melanie (2023-08-26)
    Background: Combining the GLP-1 receptor agonist semaglutide with the long-acting amylin analogue cagrilintide has weight-loss benefits; the impact on glycated haemoglobin (HbA1c) is unknown. This trial assessed the efficacy and safety of co-administered semaglutide with cagrilintide (CagriSema) in participants with type 2 diabetes. Methods: This 32-week, multicentre, double-blind, phase 2 trial was conducted across 17 sites in the USA. Adults with type 2 diabetes and a BMI of 27 kg/m2 or higher on metformin with or without an SGLT2 inhibitor were randomly assigned (1:1:1) to once-weekly subcutaneous CagriSema, semaglutide, or cagrilintide (all escalated to 2·4 mg). Randomisation was done centrally using an interactive web response system and was stratified according to use of SGLT2 inhibitor treatment (yes vs no). The trial participants, investigators, and trial sponsor staff were masked to treatment assignment throughout the trial. The primary endpoint was change from baseline in HbA1c; secondary endpoints were bodyweight, fasting plasma glucose, continuous glucose monitoring (CGM) parameters, and safety. Efficacy analyses were performed in all participants who had undergone randomisation, and safety analyses in all participants who had undergone randomisation and received at least one dose of the trial medication. This trial is registered on (NCT04982575) and is complete. Findings: Between Aug 2 and Oct 18, 2021, 92 participants were randomly assigned to CagriSema (n=31), semaglutide (n=31), or cagrilintide (n=30). 59 (64%) participants were male; the mean age of participants was 58 years (SD 9). The mean change in HbA1c from baseline to week 32 (CagriSema: -2·2 percentage points [SE 0·15]; semaglutide: -1·8 percentage points [0·16]; cagrilintide: -0·9 percentage points [0·15]) was greater with CagriSema versus cagrilintide (estimated treatment difference -1·3 percentage points [95% CI -1·7 to -0·8]; p<0·0001), but not versus semaglutide (-0·4 percentage points [-0·8 to 0·0]; p=0·075). The mean change in bodyweight from baseline to week 32 (CagriSema: -15·6% [SE 1·26]; semaglutide: -5·1% [1·26]; cagrilintide: -8·1% [1·23]) was greater with CagriSema versus both semaglutide (p<0·0001) and cagrilintide (p<0·0001). The mean change in fasting plasma glucose from baseline to week 32 (CagriSema: -3·3 mmol/L [SE 0·3]; semaglutide: -2·5 mmol/L [0·4]; cagrilintide: -1·7 mmol/L [0·3]) was greater with CagriSema versus cagrilintide (p=0·0010) but not versus semaglutide (p=0·10). Time in range (3·9-10·0 mmol/L) was 45·9%, 32·6%, and 56·9% at baseline and 88·9%, 76·2%, and 71·7% at week 32 with CagriSema, semaglutide, and cagrilintide, respectively. Adverse events were reported by 21 (68%) participants in the CagriSema group, 22 (71%) in the semaglutide group, and 24 (80%) in the cagrilintide group. Mild or moderate gastrointestinal adverse events were most common; no level 2 or 3 hypoglycaemia was reported. No fatal adverse events were reported. Interpretation: In people with type 2 diabetes, treatment with CagriSema resulted in clinically relevant improvements in glycaemic control (including CGM parameters). The mean change in HbA1c with CagriSema was greater versus cagrilintide, but not versus semaglutide. Treatment with CagriSema resulted in significantly greater weight loss versus semaglutide and cagrilintide and was well tolerated. These data support further investigation of CagriSema in this population in longer and larger phase 3 studies. Funding: Novo Nordisk.
  • Analytical performance of the factory-calibrated Flash Glucose Monitoring System FreeStyle Libre2(TM) in healthy women

    Davies, Melanie J (2023-08-25)
    Continuous glucose monitoring (CGM) is used clinically and for research purposes to capture glycaemic profiles. The accuracy of CGM among healthy populations has not been widely assessed. This study assessed agreement between glucose concentrations obtained from venous plasma and from CGM (FreeStyle Libre2TM, Abbott Diabetes Care, Witney, UK) in healthy women. Glucose concentrations were assessed after fasting and every 15 min after a standardized breakfast over a 4-h lab period. Accuracy of CGM was determined by Bland-Altman plot, 15/15% sensor agreement analysis, Clarke error grid analysis (EGA) and mean absolute relative difference (MARD). In all, 429 valid CGM readings with paired venous plasma glucose (VPG) values were obtained from 29 healthy women. Mean CGM readings were 1.14 mmol/L (95% CI: 0.97 to 1.30 mmol/L, p < 0.001) higher than VPG concentrations. Ratio 95% limits of agreement were from 0.68 to 2.20, and a proportional bias (slope: 0.22) was reported. Additionally, 45% of the CGM readings were within ±0.83 mmol/L (±15 mg/dL) or ±15% of VPG, while 85.3% were within EGA Zones A + B (clinically acceptable). MARD was 27.5% (95% CI: 20.8, 34.2%), with higher MARD values in the hypoglycaemia range and when VPG concentrations were falling. The FreeStyle Libre2TM CGM system tends to overestimate glucose concentrations compared to venous plasma samples in healthy women, especially during hypoglycaemia and during glycaemic swings.
  • Response to a low-energy meal replacement plan on glycometabolic profile and reverse cardiac remodelling in type 2 diabetes: a comparison between South Asians and White Europeans

    Athithan, Lavanya; Brady, Emer M; Davies, Melanie J; Gulsin, Guarav S; Henson, Joseph; McCann, Gerry; Parke, Kelly (2023-10-06)
    Background: South Asians (SA) constitute a quarter of the global population and are disproportionally affected by both type 2 diabetes (T2D) and heart failure. There remains limited data of the acceptability and efficacy of low-energy meal replacement plans to induce remission of T2D in SA. Objectives: The objective of this exploratory secondary analysis of the DIASTOLIC study was to determine if there was a differential uptake, glycometabolic and cardiovascular response to a low-energy meal replacement plan (MRP) between SA and White European (WE) people with T2D. Methods: Obese adults with T2D without symptomatic cardiovascular disease were allocated a low-energy (~810 kcal/day) MRP as part of the DIASTOLIC study (NCT02590822). Comprehensive multiparametric cardiovascular magnetic resonance imaging, echocardiography, cardiopulmonary exercise testing and metabolic profiling were undertaken at baseline and 12 weeks. A comparison of change at 12 weeks between groups with baseline adjustment was undertaken. Results: Fifteen WE and 12 SAs were allocated the MRP. All WE participants completed the MRP versus 8/12 (66%) SAs. The degree of concentric left ventricular remodelling was similar between ethnicities. Despite similar weight loss and reduction in liver fat percentage, SA had a lower reduction in Homeostatic Model Assessment for Insulin Resistance [-5.7 (95% CI: -7.3, -4.2) versus -8.6 (-9.7, -7.6), p = 0.005] and visceral adiposity compared to WE [-0.43% (-0.61, -0.25) versus -0.80% (-0.91, -0.68), p = 0.002]. Exercise capacity increased in WE with no change observed in SA. There was a trend towards more reverse remodelling in WE compared to SAs. Conclusions: Compliance to the MRP was lower in SA versus WE. Overall, those completing the MRP saw improvements in weight, body composition and indices of glycaemic control irrespective of ethnicity. Whilst improvements in VAT and insulin resistance appear to be dampened in SA versus WE, given the small sample, larger studies are required to confirm or challenge this potential ethnic disparity.

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