Publications by authors named "David R Webb"

69 Publications

Effects of liraglutide versus sitagliptin on circulating cardiovascular biomarkers, including circulating progenitor cells, in individuals with type 2 diabetes and obesity: Analyses from the LYDIA trial.

Diabetes Obes Metab 2021 Feb 10. Epub 2021 Feb 10.

Diabetes Research Centre, University of Leicester, Leicester, UK.

The mechanisms behind the beneficial cardiovascular effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) compared with dipeptidyl peptidase-4 inhibitors (DPP4is) remain largely unknown, despite both targeting the incretin pathway to improve glycaemic control. In these prespecified secondary analyses of the LYDIA trial, we examined the impact of the GLP-1RA liraglutide (1.8 mg once-daily) and the DPP4i sitagliptin (100 mg once-daily) on circulating cardiovascular biomarkers associated with atherosclerotic risk, including circulating progenitor cells (CPCs). LYDIA was a 26-week, randomized, active-comparator trial in 61 adults with type 2 diabetes and obesity (mean ± SD: age 43.8 ± 6.5 years, body mass index 35.3 ± 6.4 kg/m , HbA1c 7.5% ± 0.83% [58.5 ± 9.1 mmol/mol]). Vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1-alpha (SDF-1ɑ), both of which are implicated in endothelial function, were higher at 26 weeks with liraglutide therapy compared with sitagliptin (mean between-group difference [95% CI]: 77.03 [18.29, 135.77] pg/mL, p = .010; and 996.25 [818.85, 1173.64] pg/mL, p < .001, respectively). There were no between-group differences in CPCs, nitric oxide, C-reactive protein, interleukin-6, tumour necrosis factor alpha and advanced glycation end-products. These analyses suggest a favourable impact of liraglutide on VEGF and SDF-1ɑ levels compared with sitagliptin. These factors may therefore be implicated in the differential cardiovascular effects observed between these agents in large cardiovascular outcome trials. However, these are secondary analyses from a previous trial and thus hypothesis-generating. Purposive trials are required to examine these findings further.
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http://dx.doi.org/10.1111/dom.14343DOI Listing
February 2021

Association of weight loss and weight loss maintenance following diabetes diagnosis by screening and incidence of cardiovascular disease and all-cause mortality: An observational analysis of the ADDITION-Europe trial.

Diabetes Obes Metab 2021 Mar 21;23(3):730-741. Epub 2020 Dec 21.

MRC Epidemiology Unit, School of Clinical Medicine, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

Aims: Short-term weight loss may lead to remission of type 2 diabetes but the effect of maintained weight loss on cardiovascular disease (CVD) is unknown. We quantified the associations between changes in weight 5 years following a diagnosis of diabetes, and incident CVD events and mortality up to 10 years after diagnosis.

Materials And Methods: Observational analysis of the ADDITION-Europe trial of 2730 adults with screen-detected type 2 diabetes from the UK, Denmark and the Netherlands. We defined weight change based on the maintenance at 5 years of weight loss achieved during the year after diabetes diagnosis, and as 5-year overall change in weight. Incident CVD events (n = 229) and all-cause mortality (n = 225) from 5 to 10 years follow-up were ascertained from medical records.

Results: Gaining >2% weight during the year after diabetes diagnosis was associated with higher hazard of all-cause mortality versus maintaining weight [hazard ratio (95% confidence interval): 3.18 (1.30-7.82)]. Losing ≥5% weight 1 year after diagnosis was also associated with mortality, whether or not weight loss was maintained at 5 years: 2.47 (0.99-6.21) and 2.72 (1.17-6.30), respectively. Losing ≥10% weight over 5 years was associated with mortality among those with body mass index <30 kg/m [4.62 (1.87-11.42)]. Associations with CVD incidence were inconclusive.

Conclusions: Both weight loss and weight gain after screen-detected diabetes diagnosis were associated with higher mortality, but not CVD events, particularly among participants without obesity. The clinical implications of weight loss following a diagnosis of diabetes probably depend on its magnitude and timing, and may differ by body mass index status. Personalization of weight loss advice and support may be warranted.
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http://dx.doi.org/10.1111/dom.14278DOI Listing
March 2021

Where Does Metformin Stand in Modern Day Management of Type 2 Diabetes?

Pharmaceuticals (Basel) 2020 Nov 27;13(12). Epub 2020 Nov 27.

Diabetes Research Centre, University of Leicester, Leicester LE5 4PW, UK.

Metformin is the most commonly used glucose-lowering therapy (GLT) worldwide and remains the first-line therapy for newly diagnosed individuals with type 2 diabetes (T2D) in management algorithms and guidelines after the UK Prospective Diabetes Study (UKPDS) showed cardiovascular mortality benefits in the overweight population using metformin. However, the improved Major Adverse Cardiovascular Events (MACE) realised in some of the recent large cardiovascular outcomes trials (CVOTs) using sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have challenged metformin's position as a first-line agent in the management of T2D. Many experts now advocate revising the existing treatment algorithms to target atherosclerotic cardiovascular disease (ASCVD) and improving glycaemic control as a secondary aim. In this review article, we will revisit the major cardiovascular outcome data for metformin and include a critique of the UKPDS data. We then review additional factors that might be pertinent to metformin's status as a first-line agent and finally answer key questions when considering metformin's role in the modern-day management of T2D.
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http://dx.doi.org/10.3390/ph13120427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761522PMC
November 2020

Improvements in Glycemic Control After Acute Moderate-Intensity Continuous or High-Intensity Interval Exercise Are Greater in South Asians Than White Europeans With Nondiabetic Hyperglycemia: A Randomized Crossover Study.

Diabetes Care 2021 Jan 6;44(1):201-209. Epub 2020 Nov 6.

Diabetes Research Centre, University of Leicester, Leicester, U.K.

Objective: To examine whether circulating metabolic responses to low-volume high-intensity interval exercise (LV-HIIE) or continuous moderate-intensity aerobic exercise (CME) differ between white Europeans and South Asians with nondiabetic hyperglycemia (NDH).

Research Design And Methods: Thirteen white Europeans and 10 South Asians (combined median [interquartile range] age 67 [60-68] years, HbA 5.9% [5.8-6.1%] [41.0 (39.9-43.2) mmol ⋅ mol]) completed three 6-h conditions (sedentary control [CON], LV-HIIE, and CME) in a randomized order. Exercise conditions contained a single bout of LV-HIIE and CME, respectively (each ending at 2 h), with meals provided at 0 and 3 h. Circulating glucose (primary outcome), insulin, insulin resistance index (IRI), triglycerides, and nonesterified fatty acids were measured at 0, 0.5, 1, 2, 3, 3.5, 4, 5, and 6 h. Data were analyzed as postexercise time-averaged area under the curve (AUC) adjusted for age, sex, and preexercise AUC.

Results: Glucose was similar in each condition and with ethnicity, with no condition-by-ethnicity interaction ( ≥ 0.28). However, insulin was lower in LV-HIIE (mean [95% CI] -44.4 [-23.7, -65.1] mU ⋅ L) and CME (-33.8 [-13.7, -53.9] mU ⋅ L) compared with CON. Insulin responses were greater in South Asians (interaction = 0.03) such that values were similar in each ethnicity during exercise conditions, despite being 33% higher in South Asians during CON. IRI followed a similar pattern to insulin. Lipids were unaffected by exercise.

Conclusions: Reductions in insulin and insulin resistance after acute LV-HIIE and CME are greater in South Asians than in white Europeans with NDH. Further trials are required to examine the longer-term impact of LV-HIIE and CME on cardiometabolic health.
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http://dx.doi.org/10.2337/dc20-1393DOI Listing
January 2021

Adults with early-onset type 2 diabetes (aged 18-39 years) are severely underrepresented in diabetes clinical research trials.

Diabetologia 2020 08 2;63(8):1516-1520. Epub 2020 Jun 2.

Diabetes Research Centre, University of Leicester, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK.

Aims/hypothesis: Early-onset adult type 2 diabetes (diagnosed between ages 18 and 39 years) is increasingly prevalent and associated with poor long-term outcomes. We hypothesised that individuals with early-onset adult type 2 diabetes were underrepresented in the prominent research trials that underpin type 2 diabetes management guidelines.

Methods: We reviewed the mean age of the study populations recruited to 90 prominent trials in type 2 diabetes, including 37 cardio-renal outcomes trials across a range of pharmacological, non-pharmacological and multifactorial interventions, 28 trials from the phase III programmes of three representative glucose-lowering therapies used routinely in clinical practice (empagliflozin, liraglutide and sitagliptin) and 25 prominent trials of diabetes self-management education and support or intensive lifestyle interventions (diet or supervised exercise training). We then estimated the number of individuals within these trials who were aged between 18 and 39 years.

Results: Across all 90 trials, the mean age of 268,978 participants was 63 years (range 51-69 years in individual trials). In 73 trials (81%), <5% of participants were estimated to be aged 18-39 years, despite this age group representing ~15-20% of the adult type 2 diabetes population. Twenty-nine of these trials (32%; total 164,953 participants) excluded individuals below 40 years of age altogether.

Conclusions/interpretation: Guidelines for early-onset adult type 2 diabetes are extrapolated predominantly from evidence in older individuals. Strategies to support the participation of individuals with early-onset adult type 2 diabetes in future research are imperative to ensure guidelines for these high-risk individuals are evidence-based.
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http://dx.doi.org/10.1007/s00125-020-05174-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351852PMC
August 2020

Number needed to treat in cardiovascular outcome trials of glucagon-like peptide-1 receptor agonists: A systematic review with temporal analysis.

Diabetes Obes Metab 2020 09 26;22(9):1670-1677. Epub 2020 May 26.

Diabetes Research Centre, Leicester General Hospital, University of Leicester, Leicester, UK.

Cardiovascular outcome trials (CVOTs) investigating the safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) have highlighted some important differences among these medications. The recent American Diabetes Association and European Association for the Study of Diabetes consensus underlines that each trial constitutes a single experiment; therefore, it remains unclear if, and to what extent, the observed differences reflect the heterogeneous pharmacological properties of each compound. To help clarify the evidence, in this systematic review we investigated differences in trial characteristics which may have had an impact on the primary and secondary trial results, including baseline control of risk factors, prevalence of cardiovascular diseases, absolute rates of events, duration of the study, and definitions of the inclusion criteria and outcomes. Aiming at enhancing the clinical interpretation of these CVOTs, we quantified the absolute treatment effect over time in terms of the number needed to treat to avoid one major adverse cardiovascular event, showing variations among GLP-1RAs.
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http://dx.doi.org/10.1111/dom.14066DOI Listing
September 2020

A randomized, open-label, active comparator trial assessing the effects of 26 weeks of liraglutide or sitagliptin on cardiovascular function in young obese adults with type 2 diabetes.

Diabetes Obes Metab 2020 07 1;22(7):1187-1196. Epub 2020 Apr 1.

Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK.

Aim: To compare the effects of a glucagon-like peptide-1 receptor agonist and a dipeptidyl peptidase-4 inhibitor on magnetic resonance imaging-derived measures of cardiovascular function.

Materials And Methods: In a prospective, randomized, open-label, blinded endpoint trial liraglutide (1.8 mg) and sitagliptin (100 mg) were compared in asymptomatic, non-insulin treated young (aged 18-50 years) adults with obesity and type 2 diabetes. The primary outcome was difference in circumferential peak early diastolic strain rate change (PEDSR), a biomarker of cardiac diastolic dysfunction 26 weeks after randomization. Secondary outcomes included other indices of cardiac structure and function, HbA1c and body weight.

Results: Seventy-six participants were randomized (54% female, mean ± SD age 44 ± 6 years, diabetes duration 4.4 years, body mass index 35.3 ± 6.1 kg m ), of whom 65% had ≥1 cardiovascular risk factor. Sixty-one participants had primary outcome data available. There were no statistically significant between-group differences (intention-to-treat; mean [95% confidence interval]) in PEDSR change (-0.01 [-0.07, +0.06] s ), left ventricular ejection fraction (-1.98 [-4.90, +0.94]%), left ventricular mass (+1.14 [-5.23, +7.50] g) or aortic distensibility (-0.35 [-0.98, +0.28] mmHg  × 10 ) after 26 weeks. Reductions in HbA1c (-4.57 [-9.10, -0.37] mmol mol ) and body weight (-3.88 [-5.74, -2.01] kg) were greater with liraglutide.

Conclusion: There were no differences in cardiovascular structure or function after short-term use of liraglutide and sitagliptin in younger adults with obesity and type 2 diabetes. Longer studies in patients with more severe cardiac dysfunction may be necessary before definitive conclusions can be made about putative pleiotropic properties of incretin-based therapies.
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http://dx.doi.org/10.1111/dom.14023DOI Listing
July 2020

Long-term effects of intensive multifactorial therapy in individuals with screen-detected type 2 diabetes in primary care: 10-year follow-up of the ADDITION-Europe cluster-randomised trial.

Lancet Diabetes Endocrinol 2019 12;7(12):925-937

Section for General Practice, Aarhus University, Aarhus, Denmark; Steno Diabetes Center, Aarhus University Hospital, Aarhus, Denmark.

Background: The multicentre, international ADDITION-Europe study investigated the effect of promoting intensive treatment of multiple risk factors among people with screen-detected type 2 diabetes over 5 years. Here we report the results of a post-hoc 10-year follow-up analysis of ADDITION-Europe to establish whether differences in treatment and cardiovascular risk factors have been maintained and to assess effects on cardiovascular outcomes.

Methods: As previously described, general practices from four centres (Denmark, Cambridge [UK], Leicester [UK], and the Netherlands) were randomly assigned by computer-generated list to provide screening followed by routine care of diabetes, or screening followed by intensive multifactorial treatment. Population-based stepwise screening programmes among people aged 40-69 years (50-69 years in the Netherlands), between April, 2001, and December, 2006, identified patients with type 2 diabetes. Allocation was concealed from patients. Following the 5-year follow-up, no attempts were made to maintain differences in treatment between study groups. In this report, we did a post-hoc analysis of cardiovascular and renal outcomes over 10 years following randomisation, including a 5 years post-intervention follow-up. As in the original trial, the primary endpoint was a composite of first cardiovascular event, including cardiovascular mortality, cardiovascular morbidity (non-fatal myocardial infarction and non-fatal stroke), revascularisation, and non-traumatic amputation, up to Dec 31, 2014. Analyses were based on the intention-to-treat principle. ADDITION-Europe is registered with ClinicalTrials.gov, NCT00237549.

Findings: 343 general practices were randomly assigned to routine diabetes care (n=176) or intensive multifactorial treatment (n=167). 317 of these general practices (157 in the routine care group, 161 in the intensive treatment group) included eligible patients between April, 2001, and December, 2006. Of the 3233 individuals with screen-detected diabetes, 3057 agreed to participate (1379 in the routine care group, 1678 in the intensive treatment group), but at the 10-year follow-up 14 were lost to follow-up and 12 withdrew, leaving 3031 to enter 10-year follow-up analysis. Mean duration of follow-up was 9·61 years (SD 2·99). Sustained reductions over 10 years following diagnosis were apparent for bodyweight, HbA, blood pressure, and cholesterol in both study groups, but between-group differences identified at 1 and 5 years were attenuated at the 10-year follow-up. By 10 years, 443 participants had a first cardiovascular event and 465 died. There was no significant difference between groups in the incidence of the primary composite outcome (16·1 per 1000 person-years in the routine care group vs 14·3 per 1000 person-years in the intensive treatment group; hazard ratio [HR] 0·87, 95% CI 0·73-1·04; p=0·14) or all-cause mortality (15·6 vs 14·3 per 1000 person-years; HR 0·90, 0·76-1·07).

Interpretation: Sustained reductions in glycaemia and related cardiovascular risk factors over 10 years among people with screen-detected diabetes managed in primary care are achievable. The differences in prescribed treatment and cardiovascular risk factors in the 5 years following diagnosis were not maintained at 10 years, and the difference in cardiovascular events and mortality remained non-significant.

Funding: National Health Service Denmark, Danish Council for Strategic Research, Danish Research Foundation for General Practice, Novo Nordisk, Novo Nordisk Foundation, Danish Centre for Evaluation and Health Technology Assessment, Danish National Board of Health, Danish Medical Research Council, Aarhus University Research Foundation, Astra, Pfizer, GlaxoSmithKline, Servier, HemoCue, Wellcome Trust, UK Medical Research Council, UK National Institute for Health Research, UK National Health Service, Merck, Julius Center for Health Sciences and Primary Care, UK Department of Health, and Nuts-OHRA.
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http://dx.doi.org/10.1016/S2213-8587(19)30349-3DOI Listing
December 2019

The right place for Sulphonylureas today.

Diabetes Res Clin Pract 2019 Nov 31;157:107836. Epub 2019 Aug 31.

University of Leicester, Diabetes Research Centre, Leicester Diabetes Centre, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK. Electronic address:

The place of Sulphonylurea based insulin secretagogues in the management of Type 2 diabetes appears as controversial today as it was fifty years ago. Newer therapies are associated with less hypoglycaemia and weight gain than Sulphonylureas but currently cost more and lack assurances which come with long-term exposure. Emergence of recent CVOT data for SGLT-2 inhibitors and GLP-1 receptor agonists is likely to influence therapeutic choices and guidance is now supportive of their earlier use in cases at high risk of cardiovascular disease. Meta-analyses of Sulphonylurea trials have failed to indicate a consistent effect (positive or negative) on cardiovascular disease or mortality, although are limited by the relative scarcity of studies directly reporting these outcomes. The CAROLINA trial is reassuring in demonstrating cardiovascular safety for the Sulphonylurea Glimepiride when compared directly with the DPP-4 inhibitor Linagliptin, suggesting either of these agents would be relatively safe second line options after Metformin in the majority of patients. This review provides a balanced assessment of available Sulphonylurea treatments in the context of current cardiovascular outcome trial data (CVOT) data and hopefully assists informed decision making about the place of these drugs in contemporary glucose lowering practice.
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http://dx.doi.org/10.1016/j.diabres.2019.107836DOI Listing
November 2019

Efficacy of low- and very-low-energy diets in people with type 2 diabetes mellitus: A systematic review and meta-analysis of interventional studies.

Diabetes Obes Metab 2019 07 29;21(7):1695-1705. Epub 2019 Apr 29.

Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK.

Aims: To review systematically and quantify the weight loss achieved through low- (LEDs) and very-low-energy diets (VLEDs) in people with type 2 diabetes mellitus (T2DM).

Materials And Methods: Studies reporting the effects of diet-only interventions of up to 1600 kcal/d in people with T2DM were searched in MEDLINE, EMBASE and CINAHL up to July 2018. Changes in the primary (body weight and body mass index [BMI]) and secondary outcomes (glycated haemoglobin, blood lipids) according to energy restriction and duration of diet were modelled using restricted cubic splines.

Results: Forty-four studies (3817 participants) were included. The overall quality of the evidence was moderate and limited to short-term interventions up to 4 months. Baseline mean weight and BMI were 92.1 kg and 36.6 kg/m . VLEDs of 400 kcal/d led to 5.4% weight loss at 2 weeks, increasing to 17.9% at 3 months. More modest reductions of 7.3% were observed on LEDs of 1200 kcal/d and 2.0% on 1600 kcal/d after 3 months. No clear patterns emerged for secondary outcomes. Publication bias was significant for primary outcomes.

Conclusions: Through modelling, we were able to describe effective dietary deficit strategies to achieve weight reduction up to 4 months in people with T2DM. High-quality studies are required to further support clinical practice with evidence-based dietary interventions.
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http://dx.doi.org/10.1111/dom.13727DOI Listing
July 2019

Haemodynamic differences amongst women who were screened for gestational diabetes in comparison to healthy controls.

Pregnancy Hypertens 2018 Oct 27;14:23-28. Epub 2018 Jul 27.

Consultant/Honorary Senior Lecturer in Maternal and Fetal Medicine, University of Leicester, United Kingdom. Electronic address:

Aim: To assess the changes in haemodynamics amongst pregnant women who were screened for gestational diabetes mellitus (GDM) in comparison to low-risk healthy pregnant controls.

Methodology: A total of 120 pregnant women of mean (standard deviation) age 31.03 (5.41) years who attended their oral glucose tolerance test as part of the national screening for GDM (study), and 60 low-risk healthy pregnant women (control) of mean age 29.71 (5.33) years, were invited to participate in this study. All women included in the study booked at the University Hospitals of Leicester NHS Trust and fulfilled the relevant inclusion criteria. Non-invasive assessment of arterial stiffness and cardiac output were undertaken on participants between 26 and 28 weeks of pregnancy. The mean difference between GDM and low-risk group for each of the arterial stiffness and cardiac output measurements was assessed by a two-sample unpaired t-test.

Results: Significant differences were found between the study and control groups for brachial (-64.5 vs. -69.5, p < 0.04) and aortic augmentation indices (5.2 vs. 2.7, p = 0.04), though there was no significant difference for PWV (8.3 vs. 8.1, p = 0.49). Cardiac output (7.6 vs. 7.0, p = 0.011), stroke volume (84.4 vs. 76.9, p = 0.013) and central mean arterial pressure (71 vs. 58, <0.001) were also significantly different between groups. However, no significant differences were reported for heart rate, systolic and diastolic blood pressure, or total peripheral resistance.

Conclusion: Pregnant women at risk of GDM between gestational weeks 26 and 28 had significantly increased measures of arterial stiffness, as assessed by brachial and aortic augmentation indices, compared with low-risk healthy controls. Whether these women are at greater long-term cardiovascular disease risk warrants further investigation.
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http://dx.doi.org/10.1016/j.preghy.2018.07.007DOI Listing
October 2018

Cardiovascular and mortality events in type 2 diabetes cardiovascular outcomes trials: a systematic review with trend analysis.

Acta Diabetol 2019 Mar 19;56(3):331-339. Epub 2018 Nov 19.

Diabetes Research Centre, Leicester Diabetes Centre, Leicester General Hospital, Gwendolen Rd, Leicester, LE5 4PW, England, UK.

Aims: To investigate cardiovascular disease and mortality trends in control arm participants of diabetes cardiovascular outcome trials (CVOTs).

Methods: We electronically searched CVOTs published before October 2017. Data on all-cause mortality, cardiovascular mortality and events, and baseline characteristics were collected, along with study calendar years. Trends were estimated using negative binomial regressions and reported as rate ratio (RR) per 5-year intervals.

Results: 26 CVOTs, conducted from 1961 to 2015, included 86788 participants with 6543 all-cause deaths, 3265 cardiovascular deaths, and 7657 3-point major adverse cardiovascular events (3-P MACE; combined endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke). In unadjusted analysis, there was an increasing trend for 3-P MACE rates over time (5-year RR 1.57; 95% CI 1.34, 1.84); a small increasing trend for cardiovascular disease mortality rates (1.13; 1.01, 1.26); and stable rates for all-cause death. Adjusting for age, sex, previous myocardial infarction, and diabetes duration, there was no evidence of trends for 3-P MACE or cardiovascular disease mortality rates, while reducing rates were observed for nonfatal myocardial infarction (5-year RR: 0.72; 0.54, 0.96), total stroke (0.76; 0.66, 0.88), and nonfatal stroke (0.60; 0.43, 0.82).

Conclusions: In contrast to real-world data, there was no evidence of an improvement in all-cause and cardiovascular mortality in type 2 diabetes participants included in control arms of randomised clinical trials across 5 decades. Further studies should investigate whether and how dissimilarities in populations, procedures, and assessments of exposures and outcomes explain the differences between real-world setting and clinical trials.
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http://dx.doi.org/10.1007/s00592-018-1253-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394717PMC
March 2019

Cardiovascular, cancer and mortality events after bariatric surgery in people with and without pre-existing diabetes: A nationwide study.

J Diabetes 2019 Apr 7;11(4):265-272. Epub 2018 Oct 7.

Diabetes Research Centre, University of Leicester, Leicester, UK.

Background: Bariatric surgery reduces cardiovascular events and mortality risk in obese individuals. However, it is unclear whether diabetes modifies this effect. This study examined mortality, cardiovascular, and cancer risk following bariatric surgery in adults with and without pre-existing diabetes.

Methods: Using mortality-linked Hospital Episodes Statistics (2006-14) from England, the risk of death, myocardial infarction, stroke, unstable angina, heart failure, and cancer following bariatric surgery was examined; the risk of death in people undergoing surgery was also compared with mortality rates of the general population.

Results: Of the 35 887 people undergoing bariatric surgery, 9175 (25.6%) had pre-existing diabetes. During a mean follow-up of 5.3 years, 801 people died, of whom 293 (36.6%) had pre-existing diabetes. The risk of all-cause mortality was 26% higher in people with than without diabetes (adjusted hazard ratio [aHR] 1.26, 95% confidence interval [CI] 1.08-1.46), whereas the risk of cancer was 21% higher (aHR 1.21; 95% CI 1.14-1.77). The risk of cardiovascular events was higher for patients with than without diabetes (aHRs [95% CIs] 2.08 [1.42-3.05], 1.80 [1.29-2.52], 1.61 [1.18-2.19], and 1.42 [1.14-1.77] for myocardial infarction, unstable angina, stroke, and heart failure, respectively). Compared with the general population, the age-standardized mortality rate ratio was 1.70 (1.52-1.91) and 1.35 (1.23-1.48) in people with and without pre-existing diabetes, respectively.

Conclusions: For patients with pre-existing diabetes, the risk of death, cardiovascular events, and cancer after bariatric surgery was higher than for those without diabetes, whose mortality risk after surgery remains 35% higher than that of the general population.
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http://dx.doi.org/10.1111/1753-0407.12851DOI Listing
April 2019

Global burden of hypoglycaemia-related mortality in 109 countries, from 2000 to 2014: an analysis of death certificates.

Diabetologia 2018 07 1;61(7):1592-1602. Epub 2018 May 1.

Diabetes Research Centre, University of Leicester, Leicester General Hospital, Gwendolen Rd, Leicester, LE5 4PW, UK.

Aims/hypothesis: In the context of increasing prevalence of diabetes in elderly people with multimorbidity, intensive glucose control may increase the risk of severe hypoglycaemia, potentially leading to death. While rising trends of severe hypoglycaemia rates have been reported in some European, North American and Asian countries, the global burden of hypoglycaemia-related mortality is unknown. We aimed to investigate global differences and trends of hypoglycaemia-related mortality.

Methods: We used the WHO mortality database to extract information on death certificates reporting hypoglycaemia or diabetes as the underlying cause of death, and the United Nations demographic database to obtain data on mid-year population estimates from 2000 to 2014. We calculated crude and age-standardised proportions (defined as number of hypoglycaemia-related deaths divided by total number of deaths from diabetes [i.e. the sum of hypoglycaemia- and diabetes-related deaths]) and rates (hypoglycaemia-related deaths divided by mid-year population) of hypoglycaemia-related mortality and compared estimates across countries and over time.

Results: Data for proportions were extracted from 109 countries (31 had data from all years analysed [2000-2014] available). Combining all countries, the age-standardised proportion of hypoglycaemia-related deaths was 4.49 (95% CI 4.44, 4.55) per 1000 total diabetes deaths. Compared with the overall mean, most Central American, South American and (mainly) Caribbean countries reported higher proportions (five more age-standardised hypoglycaemia-related deaths per 1000 total diabetes deaths in Chile, six in Uruguay, 11 in Belize and 22 in Aruba), as well as Japan (11 more age-standardised hypoglycaemia-related deaths per 1000 total diabetes deaths). In comparison, lower proportions were noted in most European countries, the USA, Canada, New Zealand and Australia. For countries with data available for all years analysed, trend analysis showed a 60% increase in hypoglycaemia-related deaths until 2010 and stable trends onwards. Rising trends were most evident for Argentina, Brazil, Chile, the USA and Japan. Data for rates were available for 105 countries (30 had data for all years analysed [2000-2014] available). Combining all countries, the age-standardised hypoglycaemia-related death rate was 0.79 (95% CI 0.77, 0.80) per 1 million person-years. Most Central American, South American and Caribbean countries similarly reported higher rates of hypoglycaemia-related death, whilst virtually all European countries, the USA, Canada, Japan, New Zealand and Australia reported lower rates compared with the overall mean. Age-standardised rates were very low for most countries (lower than five per 1 million person-years in 89.5% of countries), resulting in small absolute differences among countries. As noted with the proportions analysis, trend analysis showed an overall 60% increase in hypoglycaemia-related deaths until 2010 and stable rate trends onwards; rising rates were particularly evident for Brazil, Chile and the USA.

Conclusions/interpretation: Most countries in South America, Central America and the Caribbean showed the highest proportions of diabetes-related deaths attributable to hypoglycaemia and the highest rates of hypoglycaemia-related deaths. Between 2000 and 2014, rising trends were observed in Brazil, Chile and the USA for both rates and proportions of hypoglycaemia-related death, and in Argentina and Japan for proportions only. Further studies are required to unravel the contribution of clinical and socioeconomic factors, difference in diabetes prevalence and heterogeneity of death certification in determining lower rates and proportions of hypoglycaemia-related deaths in high-income countries in Europe, North America and Asia.

Data Availability: Data used for these analyses are available at https://doi.org/10.17632/ndp52fbz8r.1.
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http://dx.doi.org/10.1007/s00125-018-4626-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438613PMC
July 2018

Relation of Aortic Stiffness to Left Ventricular Remodeling in Younger Adults With Type 2 Diabetes.

Diabetes 2018 07 16;67(7):1395-1400. Epub 2018 Apr 16.

Department of Cardiovascular Sciences, University of Leicester and Leicester National Institute for Health Research Biomedical Research Centre, Glenfield Hospital, Leicester, U.K.

Individuals with type 2 diabetes have a three- to fivefold increased risk of developing heart failure. Diabetic cardiomyopathy is typified by left ventricular (LV) concentric remodeling, which is a recognized predictor of adverse cardiovascular events. Although the mechanisms underlying LV remodeling in type 2 diabetes are unclear, progressive aortic stiffening may be a key determinant. The aim of this study was to assess the relationship between aortic stiffness and LV geometry in younger adults with type 2 diabetes, using multiparametric cardiovascular MRI. We prospectively recruited 80 adults (aged 18-65 years) with type 2 diabetes and no cardiovascular disease and 20 age- and sex-matched healthy control subjects. All subjects underwent comprehensive bio-anthropometric assessment and cardiac MRI, including measurement of aortic stiffness by aortic distensibility (AD). Type 2 diabetes was associated with increased LV mass, concentric LV remodeling, and lower AD compared with control subjects. On multivariable linear regression, AD was independently associated with concentric LV remodeling in type 2 diabetes. Aortic stiffness may therefore be a potential therapeutic target to prevent the development of heart failure in type 2 diabetes.
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http://dx.doi.org/10.2337/db18-0112DOI Listing
July 2018

The effects of metformin on maternal haemodynamics in gestational diabetes mellitus: A pilot study.

Diabetes Res Clin Pract 2018 May 7;139:170-178. Epub 2018 Mar 7.

University of Leicester, UK. Electronic address:

Background: Gestational diabetes mellitus (GDM) is a major clinical challenge and is likely to remain so as the incidence of GDM continues to increase.

Aim: To assess longitudinal changes in maternal haemodynamics amongst women diagnosed with GDM requiring either metformin or dietary intervention in comparison to low-risk healthy controls.

Methodology: Fifty-six pregnant women attending their first appointment at the GDM clinic and 60 low-risk healthy pregnant controls attending their routine antenatal clinics were recruited and assigned to three groups: GDM Metformin (GDM-M), GDM Diet (GDM-D) and Control. Non-invasive assessment of maternal haemodynamics, using recognised measures of arterial stiffness and central blood pressure (Arteriograph®), were undertaken under controlled conditions within four gestational windows: antenatal; AN1 (26-28 weeks), AN2 (32-34 weeks) and AN3 (37-40 weeks), and postnatal (PN) (6-8 weeks after delivery). Data were analysed using a linear mixed model incorporating gestational age and other relevant predictors, including age, blood pressure (BP), baseline bodyweight and pulse as fixed effects, and patient as a random effect.

Results: Fitted linear mixed models showed evidence of a two-way interaction effect between groups (GDM-D, GDM-M and Control) and stages of gestation (AN1, AN2, AN3 and PN) for maternal haemodynamic parameters: brachial artery augmentation index (AIx) (p = 0.004), aortic AIx (p = 0.008), and central systolic BP (p = 0.001). However, differences in respect of aortic pulse wave velocity (p = 0.001) and heart rate (p < 0.001) were only significant for gestational stage. At AN2, we did not observe any evidence that the mean brachial Aix in the GDM-M was different from the control group (p = 0.158).

Conclusion: AIx and central systolic BP measures of arterial stiffness are adversely affected by GDM in comparison to controls during pregnancy. The possible beneficial effects of metformin therapy seen at 32 to 34 weeks of gestation require further exploration.
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http://dx.doi.org/10.1016/j.diabres.2018.03.003DOI Listing
May 2018

Association between arterial stiffness and wave reflection with subsequent development of placental-mediated diseases during pregnancy: findings of a systematic review and meta-analysis.

J Hypertens 2018 05;36(5):1005-1014

Department of Maternal and Fetal Medicine, University Hospitals of Leicester, Leicester.

Objective: We present a comprehensive systematic review of published literature to examine, whether arterial stiffness and wave reflection measurements during pregnancy differed between healthy patients and patients with placental-mediated diseases including preeclampsia (PET), small for gestational age (SGA), fetal death, and placental abruption, and a quantitative assessment of the findings using the meta-analysis approach.

Methods: We searched Medline, Embase, and The Cochrane Library for studies of arterial stiffness in pregnancy, analyzed pregnancy outcomes and conducted the meta-analysis of data evaluated by trimesters of pregnancy. Hemodynamic parameters evaluated included: pulse wave velocity (PWV), augmentation index (AIx), and augmentation index-75 (AIx-75).

Results: We screened 2806 citations, reviewed 36 studies and included nine (n = 15 923) studies for further quantitative assessment. Compared with healthy pregnancy, measures of arterial stiffness and wave reflection were consistently increased among pregnant women who subsequently developed PET during all trimesters. In the first trimester, mean AIx-75 (%) in the PET group was significantly higher with estimated standardized mean difference (SMD) of 0.90 [95% confidence intervals (95% CI) 0.07-1.73; P = 0.034]. In the second trimester, the PET group had significantly higher PWV (m/s) with estimated SMD of 1.26 (95% CI 0.22-2.30; P = 0.018). Concerning the SGA group, mean AIx (%) was greater during the second trimester only: 65.5 (SD 15.6) vs. 57.0 (11.2), P < 0.01.

Conclusion: There is significant increase in arterial stiffness and wave reflection parameters among pregnant women who subsequently developed PET and SGA fetuses. Larger studies with consistent methodological designs are required to evaluate the role and usefulness of arterial stiffness and wave reflection measurements as a screening tool for placental-mediated diseases during pregnancy.
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http://dx.doi.org/10.1097/HJH.0000000000001664DOI Listing
May 2018

The influence of adiposity and acute exercise on circulating hepatokines in normal-weight and overweight/obese men.

Appl Physiol Nutr Metab 2018 May 8;43(5):482-490. Epub 2017 Dec 8.

a School of Sport, Exercise and Health Sciences, Loughborough University, Leicestershire LE11 3TU, UK.

Hepatokines are liver-secreted proteins with potential to influence glucose regulation and other metabolic parameters. This study investigated differences in adiposity status on 5 novel hepatokines and characterised their response to acute moderate-intensity exercise in groups of normal-weight and overweight/obese men. Twenty-two men were recruited into normal-weight and overweight/obese groups (body mass index: 18.5 to 24.9 and 25.0 to 34.9 kg·m). Each completed 2 experimental trials, exercise and control. During exercise trials, participants performed 60 min of moderate-intensity treadmill exercise (∼60% peak oxygen uptake) and then rested for 6 h. Participants rested throughout control trials. Circulating fibroblast growth factor-21 (FGF21), follistatin, leukocyte cell-derived chemotaxin 2 (LECT2), fetuin-A, and selenoprotein-P (SeP) were measured throughout. Fasted (resting) FGF21 and LECT2 were higher in overweight/obese individuals (129% and 55%; P ≤ 0.01) and correlated with indices of adiposity and insulin resistance; whereas circulating follistatin was lower in overweight/obese individuals throughout trial days (17%, P < 0.05). In both groups, circulating concentrations of FGF21 and follistatin were transiently elevated after exercise for up to 6 h (P ≤ 0.02). Circulating fetuin-A and SeP were no different between groups (P ≥ 0.19) and, along with LECT2, were unaffected by exercise (P ≥ 0.06). These findings show that increased adiposity is associated with a modified hepatokine profile, which may represent a novel mechanism linking excess adiposity to metabolic health. Furthermore, acute perturbations in circulating FGF21 and follistatin after exercise may contribute to the health benefits of an active lifestyle.
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http://dx.doi.org/10.1139/apnm-2017-0639DOI Listing
May 2018

Comparison of glucose-lowering agents after dual therapy failure in type 2 diabetes: A systematic review and network meta-analysis of randomized controlled trials.

Diabetes Obes Metab 2018 04 8;20(4):985-997. Epub 2018 Jan 8.

Diabetes Research Centre, University of Leicester, Leicester, UK.

Aims: To assess the evidence supporting the choice of third-line agents in adults with inadequately controlled type 2 diabetes.

Materials And Methods: We searched randomized controlled trials (RCTs) published between January 2000 and July 2017 that reported data on cardiometabolic outcomes and hypoglycaemia for glucose-lowering agents added to metformin-based dual treatments. Data were stratified by background therapy and RCT duration, and synthesized, when possible, with network meta-analyses.

Results: A total of 43 RCTs (16 590 participants) were included, with metformin combined with: sulphonylureas (SUs) in 20 RCTs; thiazolidinediones (TZDs) in 10; basal or rapid-acting insulin in 6; dipeptidyl peptidase-4 (DPP-4) inhibitors in 3; glucagon-like peptide-1 receptor agonists (GLP-1RAs) in 2; and sodium-glucose co-transporter-2 (SGLT-2) inhibitors in 2. When added to metformin and SUs, after 24 to 36 weeks, rapid-acting insulin resulted in the largest reduction in glycated haemoglobin (HbA1c; 1.6% vs placebo), followed by GLP-1RAs (1.0%), basal insulin (0.8%) and SGLT-2 inhibitors (0.7%), with no difference between GLP-1RAs and SGLT-2 inhibitors; body weight increased with insulin treatment (~3 kg vs placebo), while the greatest reduction was observed for SGLT-2 inhibitors compared with all other therapies. Limited data for hypoglycaemia indicated a similar risk for SGLT-2 inhibitors and GLP-1RAs. Results for third-line agents added to metformin and TZDs were comparable, showing similar HbA1c reduction and risk of hypoglycaemia between SGLT-2 inhibitors and GLP-1RAs, and a slightly greater reduction in body weight with SGLT-2 inhibitors vs GLP-1RAs. Data for 52 to 54 weeks were more limited: added to metformin and a SU, TZDs, GLP-1RAs or SGLT-2 inhibitors reduced HbA1c to a similar extent but had different effects on body weight (7 kg and 5 kg more with TZDs vs SGLT-2 inhibitors and GLP-1RAs, respectively; 2 kg less when comparing SGLT-2 inhibitors with GLP-1RAs). Formal analyses could not be performed for any other dual therapy failure combinations because of the small number of available RCTs.

Conclusions: Moderate-quality evidence supports the choice of a third-line agent only in patients on metformin combined with a SU or a TZD, with SGLT-2 inhibitors performing generally better than other drugs. In suggesting third-line agents, future guidelines should recognize the widely differing evidence on the various dual therapy failures.
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http://dx.doi.org/10.1111/dom.13185DOI Listing
April 2018

Longitudinal study to assess changes in arterial stiffness and cardiac output parameters among low-risk pregnant women.

Pregnancy Hypertens 2017 Oct 16;10:256-261. Epub 2017 Oct 16.

University Hospitals of Leicester, United Kingdom; University of Leicester, United Kingdom. Electronic address:

Aim: A single-centre, prospective longitudinal study to assess changes in maternal arterial stiffness and cardiac output parameters among low-risk healthy pregnant women.

Methodology: Thirty low-risk, healthy, pregnant women attending their routine antenatal dating ultrasound scan were recruited. Non-invasive assessment of arterial stiffness and cardiac output was undertaken at five gestational windows from 11 to 40 weeks of pregnancy. Data were analysed using a linear mixed model incorporating time and other relevant predictors as fixed effects, and patient as a random effect.

Results: Gestational age had a significant effect on all arterial stiffness parameters, including brachial augmentation index (AIx) (p = .001), aortic AIx (p = .002) and aortic pulse wave velocity (p = .002). The aortic AIx (%) reduced during pregnancy: the lowest mean (standard error, SE) was 4.07 (1.01) at 28 weeks before it increased to 7.04 (SE 1.64) at 40 weeks. Similarly, non-invasive assessments of cardiac output (p < .001), stroke volume (p = .014), heart rate (p < .001) and total peripheral resistance (p < .001) demonstrated significant changes with gestational age. Mean cardiac output (l/m) increased during pregnancy reaching a peak at 28 weeks gestation 6.66 (SE 0.28), but dropped thereafter to reach 5.71 (SE 0.25) around term.

Conclusion: The current study provides pregnancy normograms for gestational changes in arterial stiffness and cardiac output parameters among low-risk, healthy pregnant women. Further work will be required to assess the risk of placental mediated diseases and pregnancy outcome among pregnant women with parameters outside the normal range.
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http://dx.doi.org/10.1016/j.preghy.2017.10.007DOI Listing
October 2017

Diurnal variation and repeatability of arterial stiffness and cardiac output measurements in the third trimester of uncomplicated pregnancy.

J Hypertens 2017 12;35(12):2436-2442

aUniversity Hospitals of Leicester bDepartment of Obstetrics and Gynaecology, Health Sciences Division, University of Leicester, Leicester cDepartment of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester dSt George's University of London, and St Georges University Hospitals NHS Foundation Trust. Molecular and Clinical Sciences Research Institute, London eDiabetes Research Centre and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK.

Aim: To investigate same day repeated measures and diurnal variation of arterial stiffness, cardiac output (CO), stroke volume (SV) and total peripheral resistance (TPR) during the third trimester of normal pregnancy.

Methodology: Pulse wave velocity (PWV) and augmentation index (AIx) were recorded using the Arteriograph, while CO, SV and TPR were recorded using noninvasive cardiac output monitoring. The measurements were obtained in the third trimester of pregnancy from 21 healthy pregnant women at four time points (morning, afternoon, evening and midnight) over a 24-h period. Triplicate measurements of 67 women were obtained at 5-min intervals to assess repeatability between measurements within a patient.

Results: Diurnal measurements of arterial stiffness for brachial AIx, aortic AIx and PWV were not statistically significantly different at any of the four time points. Estimated means (SD) for PWV at the four stated time points were 7.81 (2.05), 8.45 (1.68), 7.87 (1.74) and 7.64 m/s (1.15), respectively (P = 0.267). Estimates for AIx at those time points were 10.22 (15.62), 4.44 (10.07), 6.49 (10.92) and 8.40% (8.16), respectively (P = 0.295). Similarly, mean arterial pressure, SV, SV index and TPR did not show any evidence of diurnal variation. However, we observed that the mean CO, cardiac index (CI) and heart rate (HR) varied from morning to midnight; the mean CO, HR and CI increased significantly in the afternoon compared with the corresponding mean morning measurements in a similar fashion to HR. Mean (SD) CO estimates at the four stated time points were 5.90 (1.33), 6.38 (1.49), 6.18 (1.43) and 5.80 ml/min (1.19), respectively, (P < 0.001), whereas mean CI estimates were 3.65 (0.58), 3.93 (0.68), 3.81 (0.65), and 3.57 (0.48), respectively, (P < 0.001), and mean HR estimates were 95 (12), 98 (13), 95 (12) and 88 (12.98), respectively (P < 0.001). Triplicate measurements of 61 women in our repeatability study showed moderate-to-high correlation between observations on the same woman for all Arteriograph and noninvasive cardiac output monitoring variables (estimates of intraclass correlation ranged from 0.49 to 0.91).

Conclusion: With the exception of CO, CI and HR which showed a diurnal variation, measurements of most haemodynamic parameters did not change significantly from morning to midnight, suggesting there was no evidence of systematic differences in the mean values of these variables at these time points. Multiple consecutive noninvasive measurements of vascular stiffness, CO, SV and TPR were highly correlated confirming repeatability of measurements in the third trimester of uncomplicated pregnancy, so these haemodynamic measurements do not need to be undertaken at a specific time period of the day.
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http://dx.doi.org/10.1097/HJH.0000000000001482DOI Listing
December 2017

Mini PCNL for renal calculi: does size matter?

BJU Int 2017 05;119 Suppl 5:39-46

Department of Urology, Austin Health, Heidelberg, Vic., Australia.

Objective: To evaluate the minimally invasive percutaneous nephrolithotomy (MIP) system for renal calculi.

Patients And Methods: Consecutive patients undergoing mini-percutaneous nephrolithotomy (mPCNL) procedures with the MIP system were enrolled. Patient position, American Society of Anesthesiologists classification, puncture location, stone clearance, postoperative drainage and complications were recorded, and features unique to MIP were noted.

Results: In all, 30 patients underwent 32 mPCNL procedures. The mean stone size was 17 (10.75-21.25) mm and the mean number of stones was 1 (1-2). The median stone clearance rate was 96.5 (95-100)%. The complication rate was 9.3%. No patient required a transfusion. In addition to these outcomes, we noted that the MIP system has many advantages over conventional PCNL (cPCNL). It is easy to learn and can be performed in both supine and prone positions. It is safe for supracostal puncture, provides excellent access to nearly all calyces and upper ureter, has multiple stone treatment options, can be used as an adjunct to cPCNL, and can be performed as a tubeless procedure.

Conclusion: Our experience with the MIP system has shown several advantages over cPCNL. mPCNL with the MIP system has several features that suggest it should be considered as an alternative or adjunct to cPCNL, ureteroscopy and extracorporeal shockwave lithotripsy.
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http://dx.doi.org/10.1111/bju.13839DOI Listing
May 2017

Predicting hospital stay, mortality and readmission in people admitted for hypoglycaemia: prognostic models derivation and validation.

Diabetologia 2017 06 17;60(6):1007-1015. Epub 2017 Mar 17.

Diabetes Research Centre, University of Leicester, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK.

Aims/hypothesis: Hospital admissions for hypoglycaemia represent a significant burden on individuals with diabetes and have a substantial economic impact on healthcare systems. To date, no prognostic models have been developed to predict outcomes following admission for hypoglycaemia. We aimed to develop and validate prediction models to estimate risk of inpatient death, 24 h discharge and one month readmission in people admitted to hospital for hypoglycaemia.

Methods: We used the Hospital Episode Statistics database, which includes data on all hospital admission to National Health Service hospital trusts in England, to extract admissions for hypoglycaemia between 2010 and 2014. We developed, internally and temporally validated, and compared two prognostic risk models for each outcome. The first model included age, sex, ethnicity, region, social deprivation and Charlson score ('base' model). In the second model, we added to the 'base' model the 20 most common medical conditions and applied a stepwise backward selection of variables ('disease' model). We used C-index and calibration plots to assess model performance and developed a calculator to estimate probabilities of outcomes according to individual characteristics.

Results: In derivation samples, 296 out of 11,136 admissions resulted in inpatient death, 1789/33,825 in one month readmission and 8396/33,803 in 24 h discharge. Corresponding values for validation samples were: 296/10,976, 1207/22,112 and 5363/22,107. The two models had similar discrimination. In derivation samples, C-indices for the base and disease models, respectively, were: 0.77 (95% CI 0.75, 0.80) and 0.78 (0.75, 0.80) for death, 0.57 (0.56, 0.59) and 0.57 (0.56, 0.58) for one month readmission, and 0.68 (0.67, 0.69) and 0.69 (0.68, 0.69) for 24 h discharge. Corresponding values in validation samples were: 0.74 (0.71, 0.76) and 0.74 (0.72, 0.77), 0.55 (0.54, 0.57) and 0.55 (0.53, 0.56), and 0.66 (0.65, 0.67) and 0.67 (0.66, 0.68). In both derivation and validation samples, calibration plots showed good agreement for the three outcomes. We developed a calculator of probabilities for inpatient death and 24 h discharge given the low performance of one month readmission models.

Conclusions/interpretation: This simple and pragmatic tool to predict in-hospital death and 24 h discharge has the potential to reduce mortality and improve discharge in people admitted for hypoglycaemia.
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http://dx.doi.org/10.1007/s00125-017-4235-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423930PMC
June 2017

Risk factors and outcome differences in hypoglycaemia-related hospital admissions: A case-control study in England.

Diabetes Obes Metab 2017 10 21;19(10):1371-1378. Epub 2017 Apr 21.

Diabetes Research Centre, University of Leicester, Leicester, England.

Aims: To evaluate risk factors for hospital admissions for hypoglycaemia and compare length of hospitalization, inpatient mortality and hospital readmission between hypoglycaemia- and non-hypoglycaemia-related admissions.

Materials And Methods: We used all admissions for hypoglycaemia in individuals with diabetes to English NHS hospital trusts between 2005 and 2014 (101 475 case admissions) and 3 random admissions per case in individuals with diabetes without hypoglycaemia (304 425 control admissions). Risk factors and differences in the 3 outcomes were estimated with logistic and negative binomial regressions.

Results: A U-shaped relationship between age and risk of admission for hypoglycaemia was observed until the age of 85 years; compared to the nadir at 60 years, the risk was progressively higher in younger and older patients and steadily declined after 85 years. Social deprivation (positively) and comorbidities (negatively) were associated with the risk of admission for hypoglycaemia. Compared to Caucasians, other ethnic groups had lower (Bangladeshi, Pakistani, Indians) or higher (Caribbean) risk of admission for hypoglycaemia. Length of hospitalization was 26% shorter while risk of rehospitalization was 65% higher in individuals admitted for hypoglycaemia. Compared to admissions for hypoglycaemia, risk of inpatient mortality was 50% lower for unstable angina but higher for acute myocardial infarction (3 times), acute renal failure (5 times) or pneumonia (8 times).

Conclusions: Among hospital-admitted individuals with diabetes, age, social deprivation, comorbidities and ethnicity are associated with higher frequency of hospitalization for hypoglycaemia. Admission for hypoglycaemia is associated with a greater risk of readmission, a shorter length of hospitalisation and a generally lower inpatient mortality compared to admissions for other medical conditions. These results could help in identifying at-risk groups to reduce the burden of hospitalization for hypoglycaemia.
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http://dx.doi.org/10.1111/dom.12941DOI Listing
October 2017

Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: A systematic review and mixed-treatment comparison analysis.

Diabetes Obes Metab 2017 04 17;19(4):524-536. Epub 2017 Feb 17.

Diabetes Research Centre, University of Leicester, Leicester, UK.

Aims: To compare efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in people with type 2 diabetes.

Materials And Methods: We electronically searched, up to June 3, 2016, published randomized clinical trials lasting between 24 and 32 weeks that compared a GLP-1RA (albiglutide, dulaglutide, twice-daily exenatide and once-weekly exenatide, liraglutide, lixisenatide, semaglutide and taspoglutide) with placebo or another GLP-1RA. Data on cardiometabolic and safety outcomes were analysed using a mixed-treatment comparison meta-analysis.

Results: A total of 34 trials (14 464 participants) met the inclusion criteria; no published data for semaglutide were available. Compared with placebo, all GLP-1RAs reduced glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels (reductions ranged from -0.55% and -0.73 mmol/L, respectively, for lixisenatide to -1.21% and -1.97 mmol/L, respectively, for dulaglutide). There were no differences within short-acting (twice-daily exenatide and lixisenatide) or long-acting (albiglutide, dulaglutide, once-weekly exenatide, liraglutide and taspoglutide) groups. Compared with twice-daily exenatide, dulaglutide treatment was associated with the greatest HbA1c and FPG reduction (0.51% and 1.04 mmol/L, respectively), followed by liraglutide (0.45% and 0.93 mmol/L, respectively) and once-weekly exenatide (0.38% and 0.85 mmol/L, respectively); similar reductions were found when these 3 agents were compared with lixisenatide. Compared with placebo, all GLP-1RAs except albiglutide reduced weight and increased the risk of hypoglycaemia and gastrointestinal side effects, and all agents except dulaglutide and taspoglutide reduced systolic blood pressure. When all GLP-1RAs were compared with each other, no clinically meaningful differences were observed in weight loss, blood pressure reduction or hypoglycaemia risk. Albiglutide had the lowest risk of nausea and diarrhoea and once-weekly exenatide the lowest risk of vomiting.

Conclusions: The RCTs in the present analysis show that all GLP-1RAs improve glycaemic control, reduce body weight and increase the risk of adverse gastrointestinal symptoms compared with placebo. Although there were no differences when short-acting agents were compared with each other or when long-acting agents were compared with each other, dulaglutide, liraglutide and once-weekly exenatide were superior to twice-daily exenatide and lixisenatide at lowering HbA1c and FPG levels. There were no differences in hypoglycaemia between these 3 agents, whilst once-weekly exenatide had the lowest risk of vomiting. These results, along with patient's preferences and individualized targets, should be considered when selecting a GLP-1RA.
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http://dx.doi.org/10.1111/dom.12849DOI Listing
April 2017

Nonlinear association of BMI with all-cause and cardiovascular mortality in type 2 diabetes mellitus: a systematic review and meta-analysis of 414,587 participants in prospective studies.

Diabetologia 2017 02 25;60(2):240-248. Epub 2016 Nov 25.

Diabetes Research Centre, Leicester Diabetes Centre, University of Leicester, Leicester General Hospital, Leicester, LE5 4PW, UK.

Aims/hypothesis: The relationship between BMI and mortality has been extensively investigated in the general population; however, it is less clear in people with type 2 diabetes. We aimed to assess the association of BMI with all-cause and cardiovascular mortality in individuals with type 2 diabetes mellitus.

Methods: We searched electronic databases up to 1 March 2016 for prospective studies reporting associations for three or more BMI groups with all-cause and cardiovascular mortality in individuals with type 2 diabetes mellitus. Study-specific associations between BMI and the most-adjusted RR were estimated using restricted cubic splines and a generalised least squares method before pooling study estimates with a multivariate random-effects meta-analysis.

Results: We included 21 studies including 24 cohorts, 414,587 participants, 61,889 all-cause and 4470 cardiovascular incident deaths; follow-up ranged from 2.7 to 15.9 years. There was a strong nonlinear relationship between BMI and all-cause mortality in both men and women, with the lowest estimated risk from 31-35 kg/m and 28-31 kg/m (p value for nonlinearity <0.001) respectively. The risk of mortality at higher BMI values increased significantly only in women, whilst lower values were associated with higher mortality in both sexes. Limited data for cardiovascular mortality were available, with a possible inverse linear association with BMI (higher risk for BMI <27 kg/m).

Conclusions/interpretation: In type 2 diabetes, BMI is nonlinearly associated with all-cause mortality with lowest risk in the overweight group in both men and women. Further research is needed to clarify the relationship with cardiovascular mortality and assess causality and sex differences.
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http://dx.doi.org/10.1007/s00125-016-4162-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518080PMC
February 2017

Trends in hospital admissions for hypoglycaemia in England: a retrospective, observational study.

Lancet Diabetes Endocrinol 2016 08 9;4(8):677-685. Epub 2016 Jun 9.

Diabetes Research Centre, University of Leicester, Leicester, UK.

Background: Studies in the USA and Canada have reported increasing or stable rates of hospital admissions for hypoglycaemia. Some data from small studies are available for other countries. We aimed to gather information about long-term trends in hospital admission for hypoglycaemia and subsequent outcomes in England to help widen understanding for the global burden of hospitalisation for hypoglycaemia.

Methods: We collected data for all hospital admissions listing hypoglycaemia as primary reason of admission between Jan 1, 2005, and Dec 31, 2014, using the Hospital Episode Statistics database, which contains details of all admissions to English National Health Service (NHS) hospital trusts. We calculated trends in crude and adjusted (for age, sex, ethnic group, social deprivation, and Charlson comorbidity score) admissions for hypoglycaemia; in admissions for hypoglycaemia per total hospital admissions and per diabetes prevalence in England; and in length of stay, in-hospital mortality, and 1 month readmissions for hypoglycaemia.

Findings: 79 172 people had 101 475 admissions for hypoglycaemia between 2005 and 2014, of which 72 568 (72%) occurred in people aged 60 years or older. 13 924 (18%) people had more than one admission for hypoglycaemia during the study period. The number of admissions increased steadily from 7868 in 2005, to 11 756 in 2010 (49% increase) and then remained more stable until 2014 (10 977; 39% increase from baseline, range across English regions 11-89%); the trend was similar after adjustment for risk factors, with a rate ratio of 1·53 (95% CI 1·29-1·81) for 2014 versus 2005. Admissions for hypoglycaemia per 100 000 total hospital admissions increased from 63·6 to 78·9 between 2005-06 and 2010-11 (24% increase), and then fell to 72·3 per 100 000 in 2013-14 (14% overall increase). Accounting for diabetes prevalence data, rates declined from 4·64 to 3·86 admissions per 1000 person-years with diabetes between 2010-11 and 2013-14. We were unable to compare prevalence rates with data prior to 2010, as the populations were not comparable; data were available for all individuals prior to 2010 but only for those aged 17 years or older after 2010. With some differences across regions, from 2005 to 2014, the adjusted proportion of admissions to receive same-day discharge increased by 43·8% (from 18·9 to 27·1 same-day discharges per 100 admissions); in-hospital mortality decreased by 46·3% (from 4·2 to 2·3 deaths per 100 admissions); and 1 month readmissions decreased by 63·0% (from 48·1 to 17·8 per 100 readmissions).

Interpretation: Over 10 years, hospital admissions in England for hypoglycaemia increased by 39% in absolute terms and by 14% considering the general increase in hospitalisation; however, accounting for diabetes prevalence, there was a reduction of admission rates. Hospital length of stay, mortality, and 1 month readmissions decreased progressively and consistently during the study period. Given the continuous rise of diabetes prevalence, ageing population, and costs associated with hypoglycaemia, individual and national initiatives should be implemented to reduce the burden of hospital admissions for hypoglycaemia.

Funding: None.
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http://dx.doi.org/10.1016/S2213-8587(16)30091-2DOI Listing
August 2016

Soluble Immune Response Suppressor (SIRS): Reassessing the immunosuppressant potential of an elusive peptide.

Authors:
David R Webb

Biochem Pharmacol 2016 10 31;117:1-9. Epub 2016 Mar 31.

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, United States. Electronic address:

A previously studied immunosuppressive cytokine, Soluble Immune Response Suppressor (SIRS), may have relevance to current studies of immune suppression in a variety of human disease states. Despite extensive efforts using experimental models, mainly in mice, much remains to be discovered as to how autoimmune cells in mice and humans escape normal regulation and, conversely, how tumor cells evade evoking an immune response. It is the contention of this commentary that the literature pre-2000 contain results that might inform current studies. The broadly immunosuppressive protein, SIRS, was studied extensively from the 1970s to 1990s and culminated in the determination of the n-terminal 21mer sequence of this 15kDa protein which had high homology to the short neurotoxins from sea snakes, that are canonical members of the three finger neurotoxin superfamily (3FTx). It was not until 2007 that the prophylactic administration of the synthetic N-terminal peptide of the SIRS 21mer, identical to the published sequence, was reported to inhibit or delay the development of two autoimmune diseases in mice: experimental allergic encephalomyelitis (EAE) and type I diabetes (T1D). These findings were consistent with other studies of the 3FTx superfamily as important probes in the study of mammalian pharmacology. It is the perspective of this commentary that SIRS, SIRS peptide and the anti-peptide mAb, represent useful, pharmacologically-active probes for the study of the immune response as well as in the potential treatment of autoimmune, inflammatory diseases and cancer.
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http://dx.doi.org/10.1016/j.bcp.2016.03.022DOI Listing
October 2016

Benefits and Harms of Once-Weekly Glucagon-like Peptide-1 Receptor Agonist Treatments: A Systematic Review and Network Meta-analysis.

Ann Intern Med 2016 Jan 8;164(2):102-13. Epub 2015 Dec 8.

Background: Once-weekly glucagon-like peptide-1 receptor agonists (GLP-1RAs) are new drugs for the treatment of type 2 diabetes.

Purpose: To summarize evidence for the cardiometabolic efficacy and adverse effects of once-weekly GLP-1RAs in adults with type 2 diabetes.

Data Sources: Electronic databases (PubMed, Web of Science, Cochrane Central Register of Controlled Trials, U.S. Food and Drug Administration, European Medicines Agency, ClinicalTrials.gov) and congress abstracts from inception through 26 September 2015.

Study Selection: Randomized, controlled trials (≥ 24 weeks of follow-up) studying albiglutide, dulaglutide, once-weekly exenatide, semaglutide, and taspoglutide and reporting a cardiometabolic (primary outcome, hemoglobin A1c [HbA1c]) or safety outcome.

Data Extraction: Extraction was done in duplicate, and risk of bias was assessed. No language restriction was applied.

Data Synthesis: 34 trials (21,126 participants) were included. Compared with placebo, all once-weekly GLP-1RAs reduced HbA1c and fasting plasma glucose; taspoglutide, 20 mg, once-weekly exenatide, and dulaglutide, 1.5 mg, reduced body weight. Among once-weekly GLP-1RAs, the greatest differences were found between dulaglutide, 1.5 mg, and taspoglutide, 10 mg, for HbA1c (-0.4% [95% CI, -0.7% to -0.2%]), once-weekly exenatide and albiglutide for fasting plasma glucose (-0.7 mmol/L [CI, -1.1 to -0.2 mmol/L]; -12.6 mg/dL [CI, -19.8 to -3.6 mg/dL]), and taspoglutide, 20 mg, and dulaglutide, 0.75 mg, for body weight (-1.5 kg [CI, -2.2 to -0.8]). Clinically marginal or no differences were found for blood pressure, blood lipid levels, and C-reactive protein levels. Once-weekly exenatide increased heart rate compared with albiglutide and dulaglutide (1.4 to 3.2 beats/min). Among once-weekly GLP-1RAs, the risk for hypoglycemia was similar, whereas taspoglutide, 20 mg, had the greatest risk for nausea (odds ratios, 1.9 to 5.9).

Limitation: Data were unavailable for semaglutide, definitions of outcomes were heterogeneous, the last-observation-carried-forward imputation method was used in 73% of trials, and publication bias is possible.

Conclusion: Compared with other once-weekly GLP-1RAs, dulaglutide, 1.5 mg; once-weekly exenatide; and taspoglutide, 20 mg, showed a greater reduction of HbA1c, fasting plasma glucose, and body weight. Taspoglutide, 20 mg, had the highest risk for nausea; risk for hypoglycemia among once-weekly GLP-1RAs was similar.

Primary Funding Source: Sanofi Aventis (grant to the University of Leicester).
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http://dx.doi.org/10.7326/M15-1432DOI Listing
January 2016

Pathophysiology of type 1 and type 2 diabetes mellitus: a 90-year perspective.

Postgrad Med J 2016 Feb 30;92(1084):63-9. Epub 2015 Nov 30.

Diabetes Research Centre, University of Leicester, Leicester, UK.

Diabetes mellitus is a complex metabolic disorder associated with an increased risk of microvascular and macrovascular disease; its main clinical characteristic is hyperglycaemia. The last century has been characterised by remarkable advances in our understanding of the mechanisms leading to hyperglycaemia. The central role of insulin in glucose metabolism regulation was clearly demonstrated during the early 1920s, when Banting, Best, Collip and Macleod successfully reduced blood glucose levels and glycosuria in a patient treated with a substance purified from bovine pancreata. Later, during the mid-1930s, clinical observations suggested a possible distinction between 'insulin-sensitive' and 'insulin-insensitive' diabetes. Only during the 1950s, when a reliable measure of circulating insulin was available, was it possible to translate these clinical observations into pathophysiological and biochemical differences, and the terms 'insulin-dependent' (indicating undetectable insulin levels) and 'non-insulin-dependent' (normal or high insulin levels) started to emerge. The next 30 years were characterised by pivotal progress in the field of immunology that were instrumental in demonstrating an immune-mediated loss of insulin-secreting β-cells in subjects with 'insulin-dependent' diabetes. At the same time, new experimental techniques allowing measurement of insulin 'impedance' showed a reduced peripheral effect of insulin in subjects with 'non-insulin-dependent' diabetes (insulin resistance). The difference between the two types of diabetes emerging from decades of observations and experiments was further formally recognised in 1979, when the definitions 'type I' and 'type II' diabetes were introduced to replace the former 'insulin-dependent' and 'non-insulin-dependent' terms. In the following years, many studies elucidated the natural history and temporal contribution of insulin resistance and β-cell insulin secretion in 'type II' diabetes. Furthermore, a central role for insulin resistance in the development of a cluster of cardiometabolic alterations (dyslipidaemia, inflammation, high blood pressure) was suggested. Possibly as a consequence of the secular changes in diabetes risk factors, in the last 10 years the limitation of a simple distinction between 'type I' and 'type II' diabetes has been increasingly recognised, with subjects showing the coexistence of insulin resistance and immune activation against β-cells. With the advancement of our cellular and molecular understanding of diabetes, a more pathophysiological classification that overcomes the historical and simple 'glucocentric' view could result in a better patient phenotyping and therapeutic approach.
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http://dx.doi.org/10.1136/postgradmedj-2015-133281DOI Listing
February 2016