Associations of antidiabetic drugs with diabetic retinopathy in people with type 2 diabetes: an umbrella review and meta-analysis.

Background: Diabetic retinopathy (DR) is the most frequent complication of type 2 diabetes and remains the leading cause of preventable blindness. Current clinical decisions regarding the administration of antidiabetic drugs do not sufficiently incorporate the risk of DR due to the inconclusive evidence from preceding meta-analyses. This umbrella review aimed to systematically evaluate the effects of antidiabetic drugs on DR in people with type 2 diabetes. Methods: A systematic literature search was undertaken in Medline, Embase, and the Cochrane Library (from inception till 17th May 2022) without language restrictions to identify systematic reviews and meta-analyses of randomized controlled trials or longitudinal studies that examined the association between antidiabetic drugs and DR in people with type 2 diabetes. Two authors independently extracted data and assessed the quality of included studies using the AMSTAR-2 (A MeaSurement Tool to Assess Systematic Reviews) checklist, and evidence assessment was performed using the GRADE (Grading of recommendations, Assessment, Development and Evaluation). Random-effects models were applied to calculate relative risk (RR) or odds ratios (OR) with 95% confidence intervals (CI). This study was registered with PROSPERO (CRD42022332052). Results: With trial evidence from 11 systematic reviews and meta-analyses, we found that the use of glucagon-like peptide-1 receptor agonists (GLP-1 RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), or dipeptidyl peptidase-4 inhibitors (DPP-4i) was not statistically associated with the risk of DR, compared to either placebo (RR: GLP-1 RA, 0.98, 0.89-1.08; SGLT-2i, 1.00, 95% CI 0.79-1.27; DPP-4i, 1.17, 0.99-1.39) or other antidiabetic drugs. Compared to other antidiabetic drugs, meglitinides (0.34, 0.01-8.25), SGLT-2i (0.73, 0.10-5.16), thiazolidinediones (0.92, 0.67-1.26), metformin (1.15, 0.81-1.63), sulphonylureas (1.24, 0.93-1.65), and acarbose (4.21, 0.44-40.43) were not statistically associated with the risk of DR. With evidence from longitudinal studies only, insulin was found to have a higher risk of DR than other antidiabetic drugs (OR: 2.47, 95% CI: 2.04-2.99). Conclusion: Our results indicate that antidiabetic drugs are generally safe to prescribe regarding the risk of DR among people with type 2 diabetes. Further robust and large-scale trials investigating the effects of insulin, meglitinides, and acarbose on DR are warranted. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=332052, identifier CRD42022332052.

Observational cross-sectional study of the association of poor broadband provision with demographic and health outcomes: the Wolverhampton Digital ENablement (WODEN) programme.

OBJECTIVES: The association between impaired digital provision, access and health outcomes has not been systematically studied. The Wolverhampton Digital ENablement programme (WODEN) is a multiagency collaborative approach to determine and address digital factors that may impact on health and social care in a single deprived multiethnic health economy. The objective of this study is to determine the association between measurable broadband provision and demographic and health outcomes in a defined population. DESIGN: An observational cross-sectional whole local population-level study with cohorts defined according to broadband provision. SETTING/PARTICIPANTS: Data for all residents of the City of Wolverhampton, totalling 269 785 residents. PRIMARY OUTCOMES: Poor broadband provision is associated with variation in demographics and with increased comorbidity and urgent care needs. RESULTS: Broadband provision was measured using the Broadband Infrastructure Index (BII) in 158 City localities housing a total of 269 785 residents. Lower broadband provision as determined by BII was associated with younger age (p<0.001), white ethnic status (p<0.001), lesser deprivation as measured by Index of Multiple Deprivation (p<0.001), a higher number of health comorbidities (p<0.001) and more non-elective urgent events over 12 months (p<0.001). CONCLUSION: Local municipal and health authorities are advised to consider the variations in broadband provision within their locality and determine equal distribution both on a geographical basis but also against demographic, health and social data to determine equitable distribution as a platform for equitable access to digital resources for their residents.

A 5-year assessment of the epidemiology and natural history of possible diabetes in remission.

INTRODUCTION: Type 2 diabetes is considered a chronic and progressive disease. The term diabetes in remission has no consensus definition and the question whether diabetes "remission" or "cure" can achieve any long-term benefits in people with type 2 diabetes remains unclear. The aim of our study was a review of our district wide diabetes population to determine the epidemiology and clinical characteristics of those who had a diagnosis of diabetes but did not meet the diagnostic criteria for diabetes at the point of assessment in 2014 and then to review their diabetes outcomes over a 5-year time frame. METHODS: In a whole population based non-interventional epidemiological study amongst 17,308 people with diabetes, we identified 991 with diet treated type 2 diabetes who met the baseline criteria for diabetes in remission (HbA1c < 48 mmol/mol (6.5%)). Over the next 5 years, 385 (39%) people had a cumulative HbA1c attainment of <48 mmol/mol (6.5%) and remained free of diabetes medication. RESULTS: In this erstwhile remission group only 130 (13%) were free of any vasculopathy, whilst 255 (26%) had some form of micro or macrovascular disease, of which 64 people had been without micro or macrovascular vascular complications at baseline. Only 20 people had a HbA1c consistently ≤37 mmol/mol (5.7%) who were free of diabetes vascular complications and of diabetes medication. CONCLUSIONS: The definition of 'diabetes in remission' remains unclear most especially regarding the inclusion of baseline prevalent or incident macro or microvascular disease, the durability of potential remission is poor, and the likelihood of cure is remote.

Risk of COVID-19 hospital admission and COVID-19 mortality during the first COVID-19 wave with a special emphasis on ethnic minorities: an observational study of a single, deprived, multiethnic UK health economy.

OBJECTIVES: The objective of this study was to describe variations in COVID-19 outcomes in relation to local risks within a well-defined but diverse single-city area. DESIGN: Observational study of COVID-19 outcomes using quality-assured integrated data from a single UK hospital contextualised to its feeder population and associated factors (comorbidities, ethnicity, age, deprivation). SETTING/PARTICIPANTS: Single-city hospital with a feeder population of 228 632 adults in Wolverhampton. MAIN OUTCOME MEASURES: Hospital admissions (defined as COVID-19 admissions (CA) or non-COVID-19 admissions (NCA)) and mortality (defined as COVID-19 deaths or non-COVID-19 deaths). RESULTS: Of the 5558 patients admitted, 686 died (556 in hospital); 930 were CA, of which 270 were hospital COVID-19 deaths, 47 non-COVID-19 deaths and 36 deaths after discharge; of the 4628 NCA, there were 239 in-hospital deaths (2 COVID-19) and 94 deaths after discharge. Of the 223 074 adults not admitted, 407 died. Age, gender, multimorbidity and black ethnicity (OR 2.1 (95% CI 1.5 to 3.2), p<0.001, compared with white ethnicity, absolute excess risk of <1/1000) were associated with CA and mortality. The South Asian cohort had lower CA and NCA, lower mortality compared with the white group (CA, 0.5 (0.3 to 0.8), p<0.01; NCA, 0.4 (0.3 to 0.6), p<0.001) and community deaths (0.5 (0.3 to 0.7), p<0.001). Despite many common risk factors for CA and NCA, ethnic groups had different admission rates and within-group differing association of risk factors. Deprivation impacted only the white ethnicity, in the oldest age bracket and in a lesser (not most) deprived quintile. CONCLUSIONS: Wolverhampton's results, reflecting high ethnic diversity and deprivation, are similar to other studies of black ethnicity, age and comorbidity risk in COVID-19 but strikingly different in South Asians and for deprivation. Sequentially considering population and then hospital-based NCA and CA outcomes, we present a complete single health economy picture. Risk factors may differ within ethnic groups; our data may be more representative of communities with high Black, Asian and minority ethnic populations, highlighting the need for locally focused public health strategies. We emphasise the need for a more comprehensible and nuanced conveyance of risk.

Attracting and retaining nurses through a clinical fellowship programme.

Shortages in nursing are the single biggest and most urgent workforce issue that the NHS needs to address. This article sets out the early success of the Nurse Clinical Fellowship Programme established by The Royal Wolverhampton NHS Trust. The unique programme aims to attract and retain nurses by offering a staff nurse post with supported access to academia, fully funded by the NHS Trust. To date, the Trust has attracted 90 nurses (both UK and international registered nurses) to the programme. The programme is also offered internally and the Trust has a cohort of 10 internal nursing staff enrolled onto the programme completing either their BSc (top-up) or Masters, with a second cohort of 60 internal nurses due to start in September 2019. To support international registered nurses with demonstrating their competence to meet Nursing and Midwifery Council requirements the Trust has also established an objective structured clinical examination preparation course designed to embrace and enhance the existing knowledge and skills, while guiding staff in transferring these in line with UK and Trust policies and practices.

Potential Clinical Error Arising From Use of HbA1c in Diabetes: Effects of the Glycation Gap.

The glycation gap (GGap) and the similar hemoglobin glycation index (HGI) define consistent differences between glycated hemoglobin and actual glycemia derived from fructosamine or mean blood glucose, respectively. Such a disparity may be found in a substantial proportion of people with diabetes, being >1 U of glycated HbA1c% or 7.2 mmol/mol in almost 40% of estimations. In this review we define these indices and explain how they can be calculated and that they are not spurious, being consistent in individuals over time. We evaluate the evidence that GGap and HGI are associated with variation in risk of complications and mortality and demonstrate the potential for clinical error in the unquestioning use of HbA1c. We explore the underlying etiology of the variation of HbA1c from mean glucose in blood plasma, including the potential role of enzymatic deglycation of hemoglobin by fructosamine-3-kinase. We conclude that measurement of GGap and HGI are important to diabetes clinicians and their patients in individualization of therapy and the avoidance of harm arising from consequent inappropriate assessment of glycemia and use of therapies.

Evidence That Differences in Fructosamine-3-Kinase Activity May Be Associated With the Glycation Gap in Human Diabetes.

The phenomenon of a discrepancy between glycated hemoglobin levels and other indicators of average glycemia may be due to many factors but can be measured as the glycation gap (GGap). This GGap is associated with differences in complications in patients with diabetes and may possibly be explained by dissimilarities in deglycation in turn leading to altered production of advanced glycation end products (AGEs). We hypothesized that variations in the level of the deglycating enzyme fructosamine-3-kinase (FN3K) might be associated with the GGap. We measured erythrocyte FN3K concentrations and enzyme activity in a population dichotomized for a large positive or negative GGap. FN3K protein was higher and we found a striking threefold greater activity (323%) at any given FN3K protein level in the erythrocytes of the negative-GGap group compared with the positive-GGap group. This was associated with lower AGE levels in the negative-GGap group (79%), lower proinflammatory adipokines (leptin-to-adiponectin ratio) (73%), and much lower prothrombotic PAI-1 levels (19%). We conclude that FN3K may play a key role in the GGap and thus diabetes complications such that FN3K may be a potential predictor of the risk of diabetes complications. Pharmacological modifications of its activity may provide a novel approach to their prevention.

Sensor and software use for the glycaemic management of insulin-treated type 1 and type 2 diabetes patients.

Lowering glucose levels, while avoiding hypoglycaemia, can be challenging in insulin-treated patients with diabetes. We evaluated the role of ambulatory glucose profile in optimising glycaemic control in this population. Insulin-treated patients with type 1 and type 2 diabetes were recruited into a prospective, multicentre, 100-day study and randomised to control (n = 28) or intervention (n = 59) groups. The intervention group used ambulatory glucose profile, generated by continuous glucose monitoring, to assess daily glucose levels, whereas the controls relied on capillary glucose testing. Patients were reviewed at days 30 and 45 by the health care professional to adjust insulin therapy. Comparing first and last 2 weeks of the study, ambulatory glucose profile-monitored type 2 diabetes patients (n = 28) showed increased time in euglycaemia (mean ± standard deviation) by 1.4 ± 3.5 h/day (p = 0.0427) associated with reduction in HbA1c from 77 ± 15 to 67 ± 13 mmol/mol (p = 0.0002) without increased hypoglycaemia. Type 1 diabetes patients (n = 25) showed reduction in hypoglycaemia from 1.4 ± 1.7 to 0.8 ± 0.8 h/day (p = 0.0472) associated with a marginal HbA1c decrease from 75 ± 10 to 72 ± 8 mmol/mol (p = 0.0508). Largely similar findings were observed comparing intervention and control groups at end of study. In conclusion, ambulatory glucose profile helps glycaemic management in insulin-treated diabetes patients by increasing time spent in euglycaemia and decreasing HbA1c in type 2 diabetes patients, while reducing hypoglycaemia in type 1 diabetes patients.

Non elective re-admissions to an acute hospital in people with diabetes: Causes and the potential for avoidance. The WICKED project.

INTRODUCTION: Managing people with diabetes is a health priority worldwide. Cost benefit attempts at avoiding non elective admissions (NEA) have had some success. To develop an NEA avoidance service, we audited multiple NEA in those with diabetes. METHOD: All people with diabetes who had ≥3 NEA to our hospital over 12 months were identified (n=418); 104 (1 in 4) patients were randomly selected and retrospective data collected in 98 subjects on their index (latest, 3rd) admission. RESULTS: Of 98 subjects (50 males, 60 Caucasians, 86 type 2 diabetes, aged 69±16 years).Conditions contributing to admission included: Significant co-morbidities in 95 patients (≥2 in 57, ≥4 in 24). Only 14 admission were directly due to diabetes: hypoglycaemia (5); hyperglycaemia (6); DKA (2), Infected foot ulcer (1).97 admissions were justified at the time of presentation. However whilst 78 were unavoidable, 19 were deemed avoidable amongst whom 10 were diabetes related. CONCLUSION: The majority of re-admissions were due to multi-morbidity and were often non-diabetes related. The concept of avoidability must be distinguished from point justification at the time of acute need. This would allow the prospective identification of high risk patients and requires an integrated working process to avoid NEA.

Association of glycation gap with mortality and vascular complications in diabetes.

OBJECTIVE: The "glycation gap" (G-gap), an essentially unproven concept, is an empiric measure of disagreement between HbA1c and fructosamine, the two indirect estimates of glycemic control. Its association with demographic features and key clinical outcomes in individuals with diabetes is uncertain. RESEARCH DESIGN AND METHODS: The G-gap was calculated as the difference between measured HbA1c and a fructosamine-derived standardized predicted HbA1c in 3,182 individuals with diabetes. The G-gap's associations with demographics and clinical outcomes (retinopathy, nephropathy, macrovascular disease, and mortality) were determined. RESULTS: Demographics varied significantly with G-gap for age, sex, ethnic status, smoking status, type and duration of diabetes, insulin use, and obesity. A positive G-gap was associated with retinopathy (odds ratio 1.24 [95% CI 1.01-1.52], P=0.039), nephropathy (1.55 [1.23-1.95], P<0.001), and, in a subset, macrovascular disease (1.91 [1.18-3.09], P=0.008). In Cox regression analysis, the G-gap had a "U"-shaped quadratic relationship with mortality, with both negative G-gap (1.96 [1.50-2.55], P<0.001) and positive G-gap (2.02 [1.57-2.60], P<0.001) being associated with a significantly higher mortality. CONCLUSIONS: We confirm published associations of G-gap with retinopathy and nephropathy. We newly demonstrate a relationship with macrovascular and mortality outcomes and potential links to distinct subpopulations of diabetes.

Evidence for consistency of the glycation gap in diabetes.

OBJECTIVE: Discordance between HbA(1c) and fructosamine estimations in the assessment of glycemia is often encountered. A number of mechanisms might explain such discordance, but whether it is consistent is uncertain. This study aims to coanalyze paired glycosylated hemoglobin (HbA(1c))-fructosamine estimations by using fructosamine to determine a predicted HbA(1c), to calculate a glycation gap (G-gap) and to determine whether the G-gap is consistent over time. RESEARCH DESIGN AND METHODS: We included 2,263 individuals with diabetes who had at least two paired HbA(1c)-fructosamine estimations that were separated by 10 ± 8 months. Of these, 1,217 individuals had a third pair. The G-gap was calculated as G-gap = HbA(1c) minus the standardized fructosamine-derived HbA(1c) equivalent (FHbA(1c)). The hypothesis that the G-gap would remain consistent in individuals over time was tested. RESULTS: The G-gaps were similar in the first, second, and third paired samples (0.0 ± 1.2, 0.0 ± 1.3, and 0.0 ± 1.3, respectively). Despite significant changes in the HbA(1c) and fructosamine, the G-gap did not differ in absolute or relative terms and showed no significant within-subject variability. The direction of the G-gap remained consistent. CONCLUSIONS: The G-gap appears consistent over time; thus, by inference any key underlying mechanisms are likely to be consistent. G-gap calculation may be a method of exploring and evaluating any such underlying mechanisms.

Does HbA1C predict isolated impaired fasting glycaemia in the oral glucose tolerance test in subjects with impaired fasting glycaemia?

BACKGROUND: To assess the usefulness of erythrocyte glycated haemoglobin (HbA1C) as a screening tool to identify those subjects with impaired fasting glycaemia (IFG) who do not have impaired glucose tolerance (IGT) or diabetes mellitus (DM) on a 75 g oral glucose tolerance test (OGTT). Design and methods All subjects undergoing an OGTT had HbA1C measured at baseline. Receiver operator characteristics analysis was used to identify optimal HbA1C cut-off values for diagnosing and excluding IGT and DM. RESULTS: We studied 140 subjects (69 women) with IFG (fasting capillary plasma glucose between 6.1-6.9 mmol/L). Using World Health Organisation criteria, 27 had isolated IFG, 56 had IGT and 57 had DM. HbA1C was higher (P < 0.001) in patients with DM (6.8 +/- 0.93%) when compared with those with IGT (6.3 +/- 0.68%) and isolated IFG (6.2 +/- 0.30%), but HbA1C was similar in those with IGT and isolated IFG. There was no HbA1C cut-off value differentiating isolated IFG from IGT or DM. None of the subjects with isolated IFG had HbA1C concentration of >6.8%, but 76% and 54% subjects with IGT and DM, respectively, had HbA1C of < or =6.8%. CONCLUSIONS: HbA1C measurement is of limited value in differentiating isolated IFG, IGT and DM in subjects with IFG. It cannot be used to identify which subjects with IFG do not require an OGTT.

Clinical impact of variability in HbA1c as assessed by simultaneously measuring fructosamine and use of error grid analysis.

BACKGROUND: Haemoglobin A1c (HbA1c) is the only measure of glycaemic control used for many patients with diabetes, but it has limitations and might sometimes be misleading. HbA(1c) concentrations are influenced by conditions that alter red-cell life and there is evidence that biochemical variation in intracellular glycation rates also influence HbA1c concentrations. This paper is the first to propose a method of using simultaneously measured HbA1c and fructosamine, and error grid analysis, in the clinical setting, to gain a better understanding of glycaemic control. METHODS: Cross-sectional analytical study using HbA1c and fructosamine measures on the same blood sample from 1744 patients having blood taken for hospital diabetes clinic appointments. No other selection or exclusion criteria were applied. RESULTS: The fructosamine results were converted to a HbA1c equivalent which was then compared with the HbA1c. In an Altman-Bland plot, the paired result differences ranged between -6.9% and +5.5% HbA1c with 1139 (65%), 438 (25%), 130 (8%) and 37 (2%) being < or =1%, 1-2%, 2-3% or >3% of HbA1c difference, respectively. In clinical error grid analysis, 864 (50%) results had tight concordance for clinical interpretation, 761 (43%) had one block disunity of probably little clinical significance, but 105 (6%) were two blocks and 14 (1%) were three blocks discordant. CONCLUSION: HbA1c may not accurately reflect glucose control. Our method, utilizing co-assessment with serum fructosamine, evaluates the possible clinical impact of this. We suggest the analysis used in this paper should be used routinely in diabetes practice.

Severe and disabling diabetic autonomic neuropathy: a case report.

We report a case of a woman with several and severe disabling manifestations of autonomic neuropathy in whom reasonable quality of life was established by combining continuous insulin infusion, jejunal feeding, colostomy and bladder self-catheterisation. We discuss the prevalence rates, pathophysiology, management and prognosis of this disabling condition.