ORCID Profile
0000-0003-2839-8404
Current Organisations
University of Southampton
,
University of Liverpool
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Publisher: BMJ
Date: 07-2020
DOI: 10.1136/BMJOPEN-2020-038856
Abstract: Obstructive sleep apnoea (OSA) and type 2 diabetes mellitus (T2DM) often occur concurrently, and untreated OSA may potentially lify the high risk of cardiovascular disease in T2DM. Compliance with continuous positive airway pressure (CPAP), the conventional treatment for OSA, can be poor and considering weight loss is the most effective treatment for OSA. This trial examines whether the glucagon-like peptide-1 receptor agonist liraglutide, a glucose-lowering therapy associated with significant weight loss used in T2DM, can improve the severity and symptoms of OSA. This is an outpatient, single-centred, open-labelled, prospective, phase IV randomised controlled trial in a two-by-two factorial design. One hundred and thirty-two patients with newly diagnosed OSA (apnoea–hypopnoea index (AHI) ≥15 events/hour), and existing obesity and T2DM (glycated haemoglobin (HbA 1c ) ≥47 mmol/mol), will be recruited from diabetes and sleep medicine outpatient clinics in primary and secondary care settings across Liverpool. Patients will be allocated equally, using computer-generated random, permuted blocks of unequal sizes, to each of the four treatment arms for 26 weeks: (i) liraglutide (1.8 mg once per day) alone, (ii) liraglutide 1.8 mg once per day with CPAP, (iii) CPAP alone (conventional care) or (iv) no treatment (control). The primary outcome measure is change in OSA severity, determined by AHI. Secondary outcome measures include effects on glycaemic control (glycated haemoglobin (HbA1c)), body weight and quality of life measures. Exploratory measures include measures of physical activity, MRI-derived measures of regional body composition including fat mass (abdominal subcutaneous, visceral, neck and liver fat) and skeletal muscle mass (cross-sectional analysis of thigh), indices of cardiac function (using transthoracic echocardiography) and endothelial function. The study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/1019) and it is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. ISRCTN16250774 . EUDRACT No. 2014-000988-41. UTN U1111-1139-0677.
Publisher: BMJ
Date: 06-2021
DOI: 10.1136/BMJOPEN-2020-043906
Abstract: Clinical trials are the gold standard for testing interventions. COVID-19 has further raised their public profile and emphasised the need to deliver better, faster, more efficient trials for patient benefit. Considerable overlap exists between data required for trials and data already collected routinely in electronic healthcare records (EHRs). Opportunities exist to use these in innovative ways to decrease duplication of effort and speed trial recruitment, conduct and follow-up. The National Institute of Health Research (NIHR), Health Data Research UK and Clinical Practice Research Datalink co-organised a national workshop to accelerate the agenda for ‘data-enabled clinical trials’. Showcasing successful ex les and imagining future possibilities, the plenary talks, panel discussions, group discussions and case studies covered: design/feasibility recruitment conduct/follow-up collecting benefits/harms and analysis/interpretation. Some notable studies have successfully accessed and used EHR to identify potential recruits, support randomised trials, deliver interventions and supplement/replace trial-specific follow-up. Some outcome measures are already reliably collected others, like safety, need detailed work to meet regulatory reporting requirements. There is a clear need for system interoperability and a ‘route map’ to identify and access the necessary datasets. Researchers running regulatory-facing trials must carefully consider how data quality and integrity would be assessed. An experience-sharing forum could stimulate wider adoption of EHR-based methods in trial design and execution. EHR offer opportunities to better plan clinical trials, assess patients and capture data more efficiently, reducing research waste and increasing focus on each trial’s specific challenges. The short-term emphasis should be on facilitating patient recruitment and for postmarketing authorisation trials where research-relevant outcome measures are readily collectable. Sharing of case studies is encouraged. The workshop directly informed NIHR’s funding call for ambitious data-enabled trials at scale. There is the opportunity for the UK to build upon existing data science capabilities to identify, recruit and monitor patients in trials at scale.
Publisher: American Diabetes Association
Date: 15-12-2016
DOI: 10.2337/DB16-0806
Abstract: The American Diabetes Association, JDRF, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists convened a research symposium, “The Differentiation of Diabetes by Pathophysiology, Natural History and Prognosis” on 10–12 October 2015. International experts in genetics, immunology, metabolism, endocrinology, and systems biology discussed genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, as well as complications. The participants debated how to determine appropriate therapeutic approaches based on disease pathophysiology and stage and defined remaining research gaps hindering a personalized medical approach for diabetes to drive the field to address these gaps. The authors recommend a structure for data stratification to define the phenotypes and genotypes of subtypes of diabetes that will facilitate in idualized treatment.
Publisher: Elsevier BV
Date: 08-2017
Publisher: Elsevier BV
Date: 07-2020
Publisher: BMJ
Date: 26-05-2012
DOI: 10.1136/THORAXJNL-2012-201622
Abstract: Placebo responses are complex psychobiological phenomena and often involve patient expectation of benefit. With continuous positive airway pressure (CPAP) treatment of obstructive sleep apnoea, greater hours of CPAP use are associated with reduced sleepiness. However, these open-label studies have not controlled for patient expectation of benefit derived from their knowledge of hours of device use. To investigate the relative effectiveness of the use of real or placebo CPAP on daytime sleepiness. Patient-level meta-analysis combining data on sleepiness measured by the Epworth Sleepiness Scale from three randomised placebo-controlled crossover trials. Mixed model analysis of variance was used to quantify the effects of real versus placebo device treatment, usage, their interaction and regression to the mean. Duration of real and placebo CPAP use was correlated within patients (r=0.53, p<0.001). High use of real CPAP reduced sleepiness more than high use of placebo (difference 3.0 points 95% CI 1.7 to 4.3, p<0.001) and more than low use of real CPAP (difference 3.3 95% CI 1.9 to 4.7, p<0.0001). High use of placebo was superior to low use of placebo (difference 1.5 95% CI 0.1 to 2.8, p=0.03). Twenty-nine per cent of the effect of high usage of CPAP (4.2 points 95% CI 3.3 to 5.1) was explained by the expectation of benefit effect associated with high use of placebo (1.2 points 95% CI 0.2 to 2.3). A clinically significant proportion of the effectiveness of high CPAP use in reducing sleepiness is probably caused by patient expectation of benefit.
Publisher: BMJ
Date: 20-05-2022
DOI: 10.1136/BMJ.O1285
Publisher: Massachusetts Medical Society
Date: 24-01-2019
Publisher: BMJ
Date: 2017
Publisher: Oxford University Press (OUP)
Date: 08-2020
DOI: 10.1530/EJE-20-0098
Abstract: Data suggest that metabolic health status, incorporating components of metabolic syndrome (MetS), predicts cardiovascular disease (CVD) risk better than BMI. This study explored the association of MetS and obesity with endothelial function, a prognostic risk factor for incident CVD. Forty-four participants were phenotyped according to BMI as non-obese vs obese ( or kg/m 2 ) and according to the International Diabetes Federation criteria of MetS: ≤2 criteria MetS (MetS−) vs ≥3 criteria MetS (MetS+) (1.)non-obese MetS− vs (2.) non-obese MetS+ and (3.) obese MetS − vs (4.) obese MetS + . Flow-mediated dilation (FMD), body composition including liver fat (MRI and spectroscopy), dietary intake, intensities of habitual physical activity and cardio-respiratory fitness were determined. Variables were analysed using a one-factor between-groups ANOVA and linear regression mean (95% CI) are presented. In iduals with MetS+ displayed lower FMD than those with MetS−. For non-obese in iduals mean difference between MetS+ and MetS− was 4.1% ((1.0, 7.3) P = 0.004) and obese in iduals had a mean difference between MetS+ and MetS− of 6.2% ((3.1, 9.2) P 0.001). Although there was no association between BMI and FMD ( P = 0.27), an increased number of MetS components was associated with a lower FMD ( P = 0.005), and after adjustment for age and sex, 19.7% of the variance of FMD was explained by MetS, whereas only 1.1% was explained by BMI. In this study cohort, components of MetS, rather than obesity per se , contribute to reduced FMD, which suggests a reduced bioavailability of nitric oxide and thus increased risk of CVD.
Publisher: Wiley
Date: 17-10-2023
DOI: 10.1111/OBR.13642
Publisher: Wiley
Date: 05-09-2023
DOI: 10.1111/DOM.15257
Publisher: BMJ
Date: 07-2021
DOI: 10.1136/BMJOPEN-2020-045663
Abstract: The newer glucose-lowering therapies for type 2 diabetes (T2D), the glucagon-like peptide-1 receptor agonists (GLP1-RAs) and the sodium-glucose co-transporter 2 inhibitors (SGLT2i), have additional clinical benefits beyond improving glycaemic control promoting weight loss, addressing associated cardiovascular risk factors and reducing macrovascular and microvascular complications. Considering their independent mechanisms of actions, there is a potential for significant synergy with combination therapy, yet limited data exist. This 32-week randomised, double-blind, placebo-controlled trial will gain mechanistic insight into the effects of coadministration of exenatide QW, a weekly subcutaneous GLP1-RA, with dapagliflozin, a once daily oral SGLT2i, on the dynamic, adaptive changes in energy balance, total, regional and organ-specific fat mass and multiorgan insulin sensitivity. 110 obese patients with diagnosed T2D (glycated haemoglobin, HbA 1c ≥48 mmol/mol) will be treated for 32 weeks with dapagliflozin (10 mg once daily either alone or in combination with exenatide QW (2 mg once weekly) active treatments will be compared with a control group (placebo tablet and sham injection). The primary objective of the study is to compare the adjusted mean reduction in total body fat mass (determined by dual-energy X-ray absorptiometry, DEXA) from baseline following 32 weeks of treatment with exenatide QW and dapagliflozin versus dapagliflozin alone compared with control (placebo). Secondary outcome measures include changes in (1) energy balance (energy intake and energy expenditure measured by indirect calorimetry) (2) appetite (between and within meals) and satiety quotient (3) body composition including visceral adipose tissue, subcutaneous adipose tissue, liver and pancreatic fat. Exploratory outcome measures include metabolic changes in hepatic and peripheral insulin sensitivity (using a two-stage hyperinsulinaemic, euglycaemic cl ), central nervous system responses to food images using blood oxygen level-dependent (BOLD) functional MRI (fMRI) and changes in cardiovascular function (using transthoracic echocardiography, cardiac MR and duplex ultrasonography). This study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/1147) and is conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice. Results from the study will be published in peer-reviewed scientific and open access journals and/or presented at scientific conferences and summarised for distribution to the participants. University of Liverpool. ISRCTN 52028580 EUDRACT number 2015-005242-60.
Publisher: Elsevier BV
Date: 10-2018
Publisher: Springer Science and Business Media LLC
Date: 31-07-2021
DOI: 10.1186/S12933-021-01345-Z
Abstract: Randomized, controlled cardiovascular outcome trials may not be fully representative of the management of patients with type 2 diabetes across different geographic regions. We conducted analyses of data from the multinational CVD-REAL consortium to determine the association between initiation of sodium–glucose cotransporter-2 inhibitors (SGLT-2i) and cardiovascular outcomes, including subgroup analyses based on patient characteristics. De-identified health records from 13 countries across three continents were used to identify patients newly-initiated on SGLT-2i or other glucose-lowering drugs (oGLDs). Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching for oGLD initiation. In the matched groups hazard ratios (HRs) for hospitalization for heart failure (HHF), all-cause death (ACD), the composite of HHF or ACD, myocardial infarction (MI) and stroke were estimated by country, and pooled using a weighted meta-analysis. Multiple subgroup analyses were conducted across patient demographic and clinical characteristics to examine any heterogeneity in treatment effects. Following matching, 440,599 new users of SGLT-2i and oGLDs were included in each group. Mean follow-up time was 396 days for SGLT-2i initiation and 406 days for oGLDs initiation. SGLT-2i initiation was associated with a lower risk of HHF (HR: 0.66, 95%CI 0.58–0.75 p 0.001), ACD (HR: 0.52, 95%CI 0.45–0.60 p 0.001), the composite of HHF or ACD (HR: 0.60, 95%CI 0.53–0.68 p 0.001), MI (HR: 0.85, 95%CI 0.78–0.92 p 0.001), and stroke (HR: 0.78, 95%CI 0.72–0.85 p 0.001) regardless of patient characteristics, including established cardiovascular disease, or geographic region. This CVD-REAL study extends the findings from the SGLT-2i clinical trials to the broader setting of an ethnically and geographically erse population, and across multiple subgroups. Trial registration NCT02993614
Publisher: Portland Press Ltd.
Date: 08-08-2014
DOI: 10.1042/CS20130404
Abstract: Non-alcoholic fatty liver disease (NAFLD), characterized by lipid deposition within the liver [intrahepatocellular lipid (IHCL)], is associated with insulin resistance and the metabolic syndrome (MS). It has been suggested that impaired skeletal muscle mitochondrial function may contribute to ectopic lipid deposition, and the associated MS, by altering post-prandial energy storage. To test this hypothesis, we performed a cross-sectional study of 17 patients with NAFLD [mean±S.D. age, 45±11 years body mass index (BMI), 31.6±3.4 kg/m2] and 18 age- and BMI-matched healthy controls (age, 44±11 years BMI, 30.5±5.2 kg/m2). We determined body composition by MRI, IHCL and intramyocellular (soleus and tibialis anterior) lipids (IMCLs) by proton magnetic resonance spectroscopy (1H-MRS) and skeletal muscle mitochondrial function by dynamic phosphorus magnetic resonance spectroscopy (31P-MRS) of quadriceps muscle. Although matched for BMI and total adiposity, after statistical adjustment for gender, patients with NAFLD (defined by IHCL ≥ 5.5%) had higher IHCLs (25±16% compared with 2±2% P& .0005) and a higher prevalence of the MS (76% compared with 28%) compared with healthy controls. Despite this, the visceral fat/subcutaneous fat ratio, IMCLs and muscle mitochondrial function were similar between the NAFLD and control groups, with no significant difference in the rate constants of post-exercise phosphocreatine (PCr) recovery (1.55±0.4 compared with 1.51±0.4 min−1), a measure of muscle mitochondrial function. In conclusion, impaired muscle mitochondrial function does not seem to underlie ectopic lipid deposition, or the accompanying features of the MS, in patients with NAFLD.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2019
DOI: 10.1249/MSS.0000000000001901
Abstract: To investigate whether (a) lower levels of daily physical activity (PA) and greater sedentary time accounted for contrasting metabolic phenotypes (higher liver fat resence of metabolic syndrome [METS+] vs lower liver fat/absence of metabolic syndrome [METS−]) in in iduals of similar body mass index and (b) the association of sedentary time on metabolic health and liver fat. Ninety-eight habitually active participants (53 female, 45 male age, 39 ± 13 yr body mass index 26.9 ± 5.1 kg·m −2 ), underwent assessments of PA (SenseWear armband wear time ~98%), cardiorespiratory fitness (V˙O 2 peak), body composition (magnetic resonance imaging and magnetic resonance spectroscopy) and multiorgan insulin sensitivity (oral glucose tolerance test). We undertook a) cross-sectional analysis comparing four groups: nonobese or obese, with and without metabolic syndrome (METS+ vs METS−) and b) univariate and multivariate regression for sedentary time and other levels of PA in relation to liver fat. Light, moderate, and vigorous PA did not account for differences in metabolic health between in iduals, whether nonobese or obese, although METS+ in iduals were more sedentary, with a higher number, and prolonged bouts (~1–2 h). Overall, sedentary time, average daily METS and V˙O 2 peak were each independently associated with liver fat percentage. Each additional hour of daily sedentary time was associated with a 1.15% (95% confidence interval, 1.14%–1.50%) higher liver fat content. Greater sedentary time, independent of other levels of PA, is associated with being metabolically unhealthy even in habitually active people, lesser sedentary time, and higher cardiorespiratory fitness and average daily METS is associated with lower liver fat.
Publisher: Elsevier BV
Date: 06-2022
Publisher: Springer Science and Business Media LLC
Date: 18-04-2018
DOI: 10.1007/S00125-018-4603-5
Abstract: Low physical activity levels and sedentary behaviour are associated with obesity, insulin resistance and type 2 diabetes. We investigated the effects of a short-term reduction in physical activity with increased sedentary behaviour on metabolic profiles and body composition, comparing the effects in in iduals with first-degree relatives with type 2 diabetes (FDR+ve) vs those without (FDR-ve). Forty-five habitually active participants (16 FDR+ve [10 female, 6 male] and 29 FDR-ve [18 female, 11 male] age 36 ± 14 years) were assessed at baseline, after 14 days of step reduction and 14 days after resuming normal activity. We determined physical activity (using a SenseWear armband), cardiorespiratory fitness ([Formula: see text]), body composition (dual-energy x-ray absorptiometry/magnetic resonance spectroscopy) and multi-organ insulin sensitivity (OGTT) at each time point. Statistical analysis was performed using a two-factor between-groups ANCOVA, with data presented as mean ± SD or (95% CI). There were no significant between-group differences in physical activity either at baseline or following step reduction. During the step-reduction phase, average daily step count decreased by 10,285 steps (95% CI 9389, 11,182 p < 0.001), a reduction of 81 ± 8%, increasing sedentary time by 223 min/day (151, 295 p < 0.001). Pooling data from both groups, following step reduction there was a significant decrease in whole-body insulin sensitivity (Matsuda index) (p < 0.001), muscle insulin sensitivity index (p < 0.001), cardiorespiratory fitness (p = 0.002) and lower limb lean mass (p = 0.004). Further, there was a significant increase in total body fat (p < 0.001), liver fat (p = 0.001) and LDL-cholesterol (p = 0.013), with a borderline significant increase in NEFA AUC during the OGTT (p = 0.050). Four significant between-group differences were apparent: following step reduction, FDR+ve participants accumulated 1.5% more android fat (0.4, 2.6 p = 0.008) and increased triacylglycerol by 0.3 mmol/l (0.1, 0.6 p = 0.044). After resuming normal activity, FDR+ve participants engaged in lower amounts of vigorous activity (p = 0.006) and had lower muscle insulin sensitivity (p = 0.023). All other changes were reversed with no significant between-group differences. A short-term reduction in physical activity with increased sedentary behaviour leads to a reversible reduction in multi-organ insulin sensitivity and cardiorespiratory fitness, with concomitant increases in central and liver fat and dyslipidaemia. The effects are broadly similar in FDR+ve and FDR-ve in iduals. Public health recommendations promoting physical activity should incorporate advice to avoid periods of sedentary behaviour.
Publisher: Frontiers Media SA
Date: 09-04-2021
DOI: 10.3389/FPHYS.2021.659834
Abstract: This study examined the effects of a short-term reduction in physical activity, and subsequent resumption, on metabolic profiles, body composition and cardiovascular (endothelial) function. Twenty-eight habitually active (≥10,000 steps/day) participants (18 female, 10 male age 32 ± 11 years BMI 24.3 ± 2.5 kg/m 2 ) were assessed at baseline, following 14 days of step-reduction and 14 days after resuming habitual activity. Physical activity was monitored throughout (SenseWear Armband). Endothelial function (flow mediated dilation FMD), cardiorespiratory fitness ( V . O 2 peak) and body composition including liver fat (dual-energy x-ray absorptiometry and magnetic resonance spectroscopy) were determined at each assessment. Statistical analysis was performed using one-way within subject’s ANOVA data presented as mean (95% CI). Participants decreased their step count from baseline by 10,111 steps/day (8949, 11,274 P & 0.001), increasing sedentary time by 103 min/day (29, 177 P & 0.001). Following 14 days of step-reduction, endothelial function was reduced by a 1.8% (0.4, 3.3 P = 0.01) decrease in FMD. Following resumption of habitual activity, FMD increased by 1.4%, comparable to the baseline level 0.4% (–1.8, 2.6 P = 1.00). Total body fat, waist circumference, liver fat, whole body insulin sensitivity and cardiorespiratory fitness were all adversely affected by 14 days step-reduction ( P & 0.05) but returned to baseline levels following resumption of activity. This data shows for the first time that whilst a decline in endothelial function is observed following short-term physical inactivity, this is reversed on resumption of habitual activity. The findings highlight the need for public health interventions that focus on minimizing time spent in sedentary behavior.
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.JACC.2018.03.009
Abstract: Randomized trials demonstrated a lower risk of cardiovascular (CV) events with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in patients with type 2 diabetes (T2D) at high CV risk. Prior real-world data suggested similar SGLT-2i effects in T2D patients with a broader risk profile, but these studies focused on heart failure and death and were limited to the United States and Europe. The purpose of this study was to examine a broad range of CV outcomes in patients initiated on SGLT-2i versus other glucose-lowering drugs (oGLDs) across 6 countries in the Asia Pacific, the Middle East, and North American regions. New users of SGLT-2i and oGLDs were identified via claims, medical records, and national registries in South Korea, Japan, Singapore, Israel, Australia, and Canada. Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching. Hazard ratios (HRs) for death, hospitalization for heart failure (HHF), death or HHF, MI, and stroke were assessed by country and pooled using weighted meta-analysis. After propensity-matching, there were 235,064 episodes of treatment initiation in each group ∼27% had established CV disease. Patient characteristics were well-balanced between groups. Dapagliflozin, empagliflozin, ipragliflozin, canagliflozin, tofogliflozin, and luseogliflozin accounted for 75%, 9%, 8%, 4%, 3%, and 1% of exposure time in the SGLT-2i group, respectively. Use of SGLT-2i versus oGLDs was associated with a lower risk of death (HR: 0.51 95% confidence interval [CI]: 0.37 to 0.70 p < 0.001), HHF (HR: 0.64 95% CI: 0.50 to 0.82 p = 0.001), death or HHF (HR: 0.60 95% CI: 0.47 to 0.76 p < 0.001), MI (HR: 0.81 95% CI: 0.74 to 0.88 p < 0.001), and stroke (HR: 0.68 95% CI: 0.55 to 0.84 p < 0.001). Results were directionally consistent across both countries and patient subgroups, including those with and without CV disease. In this large, international study of patients with T2D from the Asia Pacific, the Middle East, and North America, initiation of SGLT-2i was associated with a lower risk of CV events across a broad range of outcomes and patient characteristics. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL] NCT02993614).
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for John Wilding.