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Aims Diabetes can significantly impact quality of life and mental health. However, inconsistencies have been reported in the prevalence of depression in those with Type 1 and Type 2 diabetes, and those without. Systematic reviews also included studies without adequate control subjects. We update existing literature, by comparing depression prevalence between individuals with and without Type 1 and Type 2 diabetes. Methods A systematic review and meta-analysis. We searched MEDLINE, EMBASE and PSYCHINFO, from January 1985 to August 2021. Studies were excluded if they failed to have an adequate control group, specified type of diabetes, or reported depression prevalence by type of diabetes. Results 44 studies were selected for inclusion. The prevalence of depression was significantly higher in people with Type 1 (22% vs 13%, OR = 2.10 (95% CI: 1.23, 3.52)), or Type 2 diabetes (19% vs 11%, OR = 1.76 (1.55, 2.01)) compared to those without diabetes. There was no association between study effect size and mean age or gender. Findings did not significantly differ between methods of depression assessment. Prevalence of depression in people with diabetes was higher in studies carried out in specialist care (36%, OR = 3.14 (2.12, 4.63)) compared to those in community or primary care (12%, OR = 1.51 (1.35, 1.70) and in low- and middle-income countries (OR = 2.58 (1.91, 3.50) compared to countries with high income economies (OR = 1.59 (1.39, 1.82)). Conclusions Depression prevalence remains significant in those with type 1 and type 2 diabetes. Effective chronic disease management in people with diabetes is important, particularly screening and managing depression and diabetes distress in specialist care settings.

AIMS To assess the efficacy and safety of iGlarLixi (the titratable fixed-ratio combination of insulin glargine 100 U/mL [iGlar] plus lixisenatide [Lixi]), in adults with type 2 diabetes (T2D) with glycated haemoglobin (HbA1c) levels ≥8% (≥64 mmol/mol). MATERIALS AND METHODS The LixiLan-O study (NCT02058147) compared iGlarLixi with iGlar or Lixi in adults with T2D inadequately controlled on metformin ± a second oral antidiabetes drug (OAD). This exploratory analysis evaluated the LixiLan-O subgroup of participants with baseline HbA1c levels of ≥8% (≥64 mmol/mol) who were receiving metformin plus a second OAD at screening. RESULTS The mean diabetes duration was 10.0 years, and the mean duration of second OAD use was 4.5 years. iGlarLixi demonstrated greater mean reductions from baseline in HbA1c and 2-hour postprandial glucose (PPG) compared with iGlar or Lixi (HbA1c -1.9% vs. -1.6% or -1.0% [-20 vs. -17 or -10 mmol/mol; 2-hour PPG -7.2 vs. -4.6 or -5.5 mmol/L). Greater proportions of participants achieved HbA1c

Background: Identifying clusters of physical activity (PA) from accelerometer data is important to identify levels of sedentary behaviour and physical activity associated with risks of serious health conditions and time spent engaging in healthy PA. Unsupervised machine learning models can capture PA in everyday free-living activity without the need for labelled data. However, there is scant research addressing the selection of features from accelerometer data. The aim of this systematic review is to summarise feature selection techniques applied in studies concerned with unsupervised machine learning of accelerometer-based device obtained physical activity, and to identify commonly used features identified through these techniques. Feature selection methods can reduce the complexity and computational burden of these models by removing less important features and assist in understanding the relative importance of feature sets and individual features in clustering. Method: We conducted a systematic search of Pubmed, Medline, Google Scholar, Scopus, Arxiv and Web of Science databases to identify studies published before January 2021 which used feature selection methods to derive PA clusters using unsupervised machine learning models. Results: A total of 13 studies were eligible for inclusion within the review. The most popular feature selection techniques were Principal Component Analysis (PCA) and correlation-based methods, with k-means frequently used in clustering accelerometer data. Cluster quality evaluation methods were diverse, including both external(e.g. cluster purity) or internal evaluation measures (silhouette score most frequently). Only four of the 13studies had more than 25 participants and only four studies included two or more datasets. Conclusion: There is a need to assess multiple feature selection methods upon large cohort data consisting of multiple (3 or more) PA datasets. The cut-off criteria e.g. number of components, pairwise correlation value, explained variance ratio for PCA, etc. should be expressly stated along with any hyperparameters used in clustering. Refereed/Peer-reviewed

Microvascular complications of diabetes present a significant challenge due to their diverse presentations, significant morbidity, and as strong predictors of cardiovascular disease. Prevention and management strategies should focus on lifestyle modification, education and awareness, systematic screening for early complications, and intensive management of modifiable risk factors. This review discusses the microvascular complications of diabetes, including diabetic retinopathy, diabetic kidney disease, and diabetic neuropathy, and provides best practice clinical care recommendations to guide health care professionals to better manage people with these conditions.

Background Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist that is under development for the treatment of type 2 dia...

Aims/Introduction The aim of this study was to examine ethnicity‐specific associations between type 2 diabetes mellitus and the risk of a cardiovascular disease (CVD) event as well as risk of specific CVD phenotypes in England. Methods We obtained data from the Clinical Practice Research Datalink for adults with and without type 2 diabetes mellitus diagnosed 2000–2006. The outcome was the first CVD event during 2007–2017 and the following components: aortic aneurysm, cerebrovascular accidents, heart failure, myocardial infarction, peripheral vascular disease and other CVD‐related conditions. Flexible parametric survival models were used to estimate ethnicity‐specific adjusted hazard ratios. Results A total of 734,543 people with and without type 2 diabetes mellitus (29,847; 4.1%) were included; most were of white ethnicity (93.0% with and 92.3% without type 2 diabetes mellitus) followed by South Asian (3.2 and 4.6%). During a median follow‐up period of 11.0 years, 67,218 events occurred (6,156 in individuals with type 2 diabetes mellitus). Type 2 diabetes mellitus was associated with a small increase in CVD events (adjusted hazard ratio 1.06, 95% confidence interval 1.02–1.09) in individuals of white ethnicity; whereas the adjusted hazard ratios were considerably higher in individuals of South Asian ethnicity (1.28, 95% confidence interval 1.09–1.51), primarily due to an increased risk of myocardial infarction (1.53, 95% confidence interval 1.08–2.18). Conclusions Despite universal access to healthcare, there are large disparities in CVD outcomes in people with and without type 2 diabetes mellitus. Other non‐traditional risk factors might play a role in the higher CVD risk associated with type 2 diabetes mellitus in individuals of South Asian ethnicity., Despite universal access to healthcare, there are large ethnic disparities in cardiovascular disease outcomes in people with and without type 2 diabetes mellitus. Type 2 diabetes mellitus was associated with a small increase in cardiovascular disease events (adjusted hazard ratio 1.06, 95% confidence interval 1.02–1.09) in individuals of white ethnicity; whereas the adjusted hazard ratio was considerably higher in individuals of South Asian ethnicity (1.28, 95% confidence interval 1.09–1.51), primarily due to an increased risk of myocardial infarction (adjusted hazard ratio 1.53, 95% confidence interval 1.08–2.18).

Within the last decade, clustering of comorbidities has become an increasing health problem on a global scale and will continue to challenge healthcare professionals in the coming years. People with multiple diseases find difficulties in managing their daily lives due to the implications each disease brings; attending and keeping up to date with hospital appointments, being prescribed and taking various medications, the effects of mental health and quality of life, and the impact it has on their families. Most research in clinical trials often exclude individuals with multimorbidity and observational studies mainly focus on single disease outcomes, therefore there is an opportunity to encourage future research in an area which could help prevent further cases and improve the lives of those already living with multimorbidity. This review aims to summarise the rising prevalence and most common clusters, highlight the challenges faced in healthcare, and explore ways to improve future research.

Background Although age, obesity and pre-existing chronic diseases are established risk factors for COVID-19 outcomes, their interactions have not been well researched. Methods We used data from the Clinical Characterisation Protocol UK (CCP-UK) for Severe Emerging Infection developed by the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC). Patients admitted to hospital with COVID-19 from 6th February to 12th October 2020 were included where there was a coded outcome following hospital admission. Obesity was determined by an assessment from a clinician and chronic disease by medical records. Chronic diseases included: chronic cardiac disease, hypertension, chronic kidney disease, chronic pulmonary disease, diabetes and cancer. Mutually exclusive categories of obesity, with or without chronic disease, were created. Associations with in-hospital mortality were examined across sex and age categories. Results The analysis included 27,624 women with 6407 (23.2%) in-hospital deaths and 35,065 men with 10,001 (28.5%) in-hospital deaths. The prevalence of chronic disease in women and men was 66.3 and 68.5%, respectively, while that of obesity was 12.9 and 11.1%, respectively. Association of obesity and chronic disease status varied by age (p Conclusion Obesity and chronic disease are important risk factors for in-hospital mortality in younger age groups, with the combination of chronic disease and obesity being particularly important in those under 50 years of age. These findings have implications for targeted public health interventions, vaccination strategies and in-hospital clinical decision making.

Exercise, Pharmaceutical Therapies and Type 2 Diabetes: Looking beyond Glycemic Control to Whole Body Health and Function Thomas Yates()1,2, Joseph Henson1,2, Jack Sargeant1,2, James A King2,4, Ehtasham Ahmad1, Francesco Zaccardi1,3 and Melanie J Davies1,2 1Diabetes Research Center, University of Leicester, Leicester General Hospital, Leicester, LE5 4PW, UK 2NIHR Leicester Biomedical Research Center, University Hospitals of Leicester NHS Trust and University of Leicester, UK 3Leicester Real World Evidence Unit, Diabetes Research Center, University of Leicester, Leicester, UK 4National Center for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, UK © The Authors Abstract Exercise is a powerful therapy for improving glycemic control and increasing cardiorespiratory fitness in adults with type 2 diabetes mellitus (T2DM). However, there is a dearth of evidence investigating interactions or synergies between exercise and most pharmaceutical therapies. This is important as exercise is rarely prescribed in isolation of other background medications used to manage T2DM. Therefore understanding which exercise and drug combinations optimize or blunt responses is crucial. This narrative review discusses advances in weight loss management in diabetes and highlights research opportunities and challenges for combining exercise therapies with newer generations of glucose-lowering therapies with weight loss effects, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is). We discuss the role of exercise in preserving lean mass and increasing physical function along with other potential areas of synergy. We conclude that until the evidence base investigating areas of interaction or synergy between exercise and other glucose-lowering or weight loss therapies is developed, exercise will remain a generic rather than a tailored therapy in the management of T2DM.

Objective To assess whether the presence of microvascular complications modifies the effect of intensive glucose reduction on long-term outcomes in patients with type 2 diabetes. Patients and Methods Using ACCORD and ACCORDION study data, we investigated the risk of the primary outcome (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) or death in relation to the prerandomization type and extent of microvascular complications. Interaction terms were fitted in survival models to estimate the risk of both outcomes across levels of an overall microvascular disease score (range 0 to 100) and its individual components: diabetic nephropathy, retinopathy, and neuropathy. Results During a mean follow-up of 7.7 years, 1685 primary outcomes and 1806 deaths occurred in 9405 participants. The outcome-specific microvascular score was ≤30 in 97.9% of subjects for the primary outcome and in 98.5% for death. For participants with scores of 0 and 30, respectively, the 10-year absolute risk difference between intensive glucose control and standard treatment ranged from −0.8% (95% CI, −2.6, 1.1) to −3.0% −7.1, 1.1) for the primary outcome and from −0.5% (−2.1, 1.1) to 0.7% (−4.2, 5.6) for mortality. Retinopathy was associated with the largest effects, with a 10-year absolute risk difference of −6.5% (−11.1 to −2.0) for the primary outcome and −3.9% (−7.8 to 0.1) for mortality. Conclusion This hypothesis-generating study identifies diabetic retinopathy as predictor of the beneficial effect of intensive glucose control on the risk of cardiovascular disease and possibly death. Further long-term studies are required to confirm these findings.

Background Type 2 diabetes, which contributes 90% of all cases of diabetes mellitus is now mostly managed in the primary care settings in the UK and other advanced health care systems. The UK National Health Service as a whole could potentially benefit if more patients were managed in primary care settings since primary care‐based care is likely to be more cost‐effective. We initially compared eight larger general practices (Enhanced practices) in Leicester, UK with neighbouring smaller practices (Core practices) matched for comparable demographic characteristics. Even though this initial study did not find any statistically significant differences in terms of clinical outcomes there was trend in favour of the enhanced practices. In this current study, we conducted a cost comparison of enhanced practice model of diabetes care, to standard care delivered in the core practices. Methods Data and information were combined from a number of sources and a cost comparison evaluation was carried out in WinBUGs. A probabilistic approach was taken, to allow uncertainty to be included around analysis parameters where appropriate. The analysis evaluated a straight-forward cost comparison of enhanced versus standard care. Results The cost per person with diabetes per year was £255 (95% CrI 175, 380) in the core practices and £173 (95% CrI 96, 291) in the enhanced practices, resulting in an annual cost saving of –£83 (95% CrI -148, -28) per patient. If the enhanced model of diabetes care were delivered across all the practices in the UK, the cost would be £575,100,000 (95% CrI 320,700,000, 970,700,000), resulting in an annual cost saving of -276,200,000 (95% CrI -495,400,000, -94,480,000). Conclusion A cost comparison analysis of our larger enhanced primary care based diabetes service confirms significant cost saving, probably driven by economies of scale. These benefits could be multiplied manifold if the service was implemented nationally.

Background The impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health is still being unravelled. It is important to identify which individuals are at greatest risk of worsening symptoms. This study aimed to examine changes in depression, anxiety and post-traumatic stress disorder (PTSD) symptoms using prospective and retrospective symptom change assessments, and to find and examine the effect of key risk factors. Method Online questionnaires were administered to 34 465 individuals (aged 16 years or above) in April/May 2020 in the UK, recruited from existing cohorts or via social media. Around one-third (n = 12 718) of included participants had prior diagnoses of depression or anxiety and had completed pre-pandemic mental health assessments (between September 2018 and February 2020), allowing prospective investigation of symptom change. Results Prospective symptom analyses showed small decreases in depression (PHQ-9: −0.43 points) and anxiety [generalised anxiety disorder scale – 7 items (GAD)-7: −0.33 points] and increases in PTSD (PCL-6: 0.22 points). Conversely, retrospective symptom analyses demonstrated significant large increases (PHQ-9: 2.40; GAD-7 = 1.97), with 55% reported worsening mental health since the beginning of the pandemic on a global change rating. Across both prospective and retrospective measures of symptom change, worsening depression, anxiety and PTSD symptoms were associated with prior mental health diagnoses, female gender, young age and unemployed/student status. Conclusions We highlight the effect of prior mental health diagnoses on worsening mental health during the pandemic and confirm previously reported sociodemographic risk factors. Discrepancies between prospective and retrospective measures of changes in mental health may be related to recall bias-related underestimation of prior symptom severity.

Objective Assessment of sitting has been challenging and nuances in the length of sitting are often missed. Methods The present study assessed total, short and prolonged sitting time, and number of breaks from sitting, and their association with anxiety, depression, and health-related quality of life (HRQoL). Adults (M=59.1 years) in three studies (n=1,574) wore the activPAL accelerometer (thigh) to obtain a measure of sitting, and the Actigraph accelerometer (hip) for estimating moderate-to-vigorous physical activity (MVPA). Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale, and HRQoL using the EQ-5D-5L (for health state and utility scores). Generalised linear modelling tested associations. Results Total and prolonged sitting were associated with higher depression [total: β = 0.132 (0.010, 0.254); prolonged: β = 0.178 (0.053, 0.304)] and worse HRQoL health state scores [(total: β = -0.985 (-1.471, -0.499); prolonged: β = -0.834 (-1.301, -0.367)] and utility scores [(total: β = -0.008 (-0.012, -0.003); prolonged: β = -0.008 (-0.012, -0.004)], after controlling for covariates. MVPA was associated with better HRQoL health state and utility scores [health state: β =0.554 (0.187, 0.922); utility: β = 0.001 (0.001, 0.002)]. Total and prolonged sitting were associated with a 14% increased odds of being in the borderline/abnormal category for depression. No interactions were observed between MVPA status (active vs. inactive) and total or prolonged sitting. Anxiety was unrelated to any sitting variable. Conclusion Device-based measures of both total and prolonged sitting time were associated with depression and health-related quality of life, but not anxiety.

Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

Background Trimethylamine N-oxide (TMAO), a metabolite generated by the gut in response (in part) to meat consumption, is linked to poor cardiometabolic health. Objectives We investigate the effect of an 8-week vegan diet, followed by a 4-week period of unrestricted diet, on glucose tolerance and plasma TMAO in human omnivores with obesity or dysglycemia. Methods This interventional single-group prospective trial involved 23 regular meat eaters with dysglycemia [glycated hemoglobin ≥ 5.7% and ≤8% (39-64 mmol/mol)], or obesity (ΒΜΙ ≥ 30 kg/m2) aged 57.8 ± 10.0 years. Participants [14 men (60.9%) and 9 women (39.1%)] were supported in following a vegan diet for 8 weeks, followed by 4 weeks of unrestricted diet. The primary outcomes (plasma TMAO and glucose) were assessed at baseline, during the vegan diet (weeks 1 and 8), and after the unrestricted diet period (week 12). TMAO was assessed after fasting and glucose was measured as a time-averaged total AUC using a 180-minute oral-glucose-tolerance test. Generalized estimating equation models with an exchangeable correlation structure were used to assess changes from baseline, adjusting for age, sex, ethnicity, and weight. Results TMAO levels (marginal mean) were reduced after weeks 1 and 8 of a vegan diet compared to baseline, from 10.7 (97.5% CI, 6.61-17.3) μmol/L to 5.66 (97.5% CI, 4.56-7.02) μmol/L and 6.38 (97.5% CI, 5.25-7.74) μmol/L, respectively; however, levels rebounded at week 12 after resumption of an unrestricted diet (17.5 μmol/L; 97.5% CI, 7.98-38.4). Postprandial glucose levels (marginal means) were reduced after weeks 1 and 8 compared to baseline, from 8.07 (97.5% CI, 7.24-8.90) mmol/L to 7.14 (97.5% CI, 6.30-7.98) mmol/L and 7.34 (97.5% CI, 6.63-8.04) mmol/L, respectively. Results for glucose and TMAO were independent of weight loss. Improvements in the lipid profile and markers of renal function were observed at week 8. Conclusions These findings suggest that a vegan diet is an effective strategy for improving glucose tolerance and reducing plasma TMAO in individuals with dysglycemia or obesity. This study was registered at clinicaltrials.gov as NCT03315988.

Obesity is an emerging risk factor for coronavirus disease-2019 (COVID-19). Simple measures of physical fitness, such as self-reported walking pace, may also be important risk markers. This analysis includes 412,596 UK Biobank participants with linked COVID-19 data (median age at linkage = 68 years, obese = 24%, median number of comorbidities = 1). As of August 24th 2020, there were 1001 cases of severe (in-hospital) disease and 336 COVID-19 deaths. Compared to normal weight individuals, the adjusted odds ratio (OR) of severe COVID-19 in overweight and obese individuals was 1.26 (1.07, 1.48) and 1.49 (1.25, 1.79), respectively. For COVID-19 mortality, the ORs were 1.19 (0.88, 161) and 1.82 (1.33, 2.49), respectively. Compared to those with a brisk walking pace, the OR of severe COVID-19 for steady/average and slow walkers was 1.13 (0.98, 1.31) and 1.88 (1.53, 2.31), respectively. For COVID-19 mortality, the ORs were 1.44 (1.10, 1.90) and 1.83 (1.26, 2.65), respectively. Slow walkers had the highest risk regardless of obesity status. For example, compared to normal weight brisk walkers, the OR of severe disease and COVID-19 mortality in normal weight slow walkers was 2.42 (1.53, 3.84) and 3.75 (1.61, 8.70), respectively. Self-reported slow walkers appear to be a high-risk group for severe COVID-19 outcomes independent of obesity.

Introduction: This study examined the equivalency of sleep estimates from Axivity, GENEActiv, and ActiGraph accelerometers worn on the nondominant and dominant wrists and with and without using a sleep log to guide the algorithm. Methods: 47 young adults wore an Axivity, GENEActiv, and ActiGraph accelerometer continuously on both wrists for 4–7 days. Sleep time, sleep window, sleep efficiency, sleep onset, and wake time were produced using the open-source software (GGIR). For each outcome, agreement between accelerometer brands, dominant and nondominant wrists, and with and without use of a sleep log, was examined using pairwise 95% equivalence tests (±10% equivalence zone) and intraclass correlation coefficients (ICCs), with 95% confidence intervals and limits of agreement. Results: All sleep outcomes were within a 10% equivalence zone irrespective of brand, wrist, or use of a sleep log. ICCs were poor to good for sleep time (ICCs ≥ .66) and sleep window (ICCs ≥ .56). Most ICCs were good to excellent for sleep efficiency (ICCs ≥ .73), sleep onset (ICCs ≥ .88), and wake time (ICCs ≥ .87). There were low levels of mean bias; however, there were wide 95% limits of agreement for sleep time, sleep window, sleep onset, and wake time outcomes. Sleep time (up to 25 min) and sleep window (up to 29 min) outcomes were higher when use of the sleep log was not used. Conclusion: The present findings suggest that sleep outcomes from the Axivity, GENEActiv, and ActiGraph, when analyzed identically, are comparable across studies with different accelerometer brands and wear protocols at a group level. However, caution is advised when comparing studies that differ on sleep log availability.

Background Adequate footwear fit is critical in preventing diabetes-related foot ulcers. One important element is the toe gap, the difference between foot length and internal footwear length available to the foot. We summarised the literature on toe gaps in studies assessing footwear worn by people with diabetes, the methods used to measure both foot length and internal footwear length and identify ambiguities which may impact on toe gap assessment in clinical practice, and suggest pragmatic solutions. Methods The Google Scholar database was searched to April 2020 for peer-reviewed studies using keywords related to incorrectly fitting or ill-fitting and diabetes, foot and ulcer which returned 979 results. Included studies within this narrative review encompassed toe gap measurement to assess footwear worn by people with diabetes. Results A total of eight studies were included after full paper review. Toe gap ranges as used in assessments of footwear worn by people with diabetes vary, with a minimum of 1.0–1.6 cm and a maximum of 1.5–2.0 cm, as do methods of measuring internal footwear length. Only three published studies suggested possible measuring devices. Conclusions Toe gap ranged as used when assessing footwear fit in people with diabetes vary and a gold standard device for internal footwear length measurement has yet to emerge. International guidelines provide welcome standardisation, but further research is needed to evaluate both the effect of toe gap ranges upon pressure, plantar stress response and ulceration and available measuring devices to facilitate development of toe gap measurement protocols that may further enhance consistency in practical assessments.

Aim To investigate the association of different categories of baseline cardio‐metabolic risk factors on the treatment effects of empagliflozin 10 and 25 mg when added as second‐line therapy to metformin in patients with type 2 diabetes (T2D). Materials and Methods Patients aged 18 years or older with HbA1c 7.0%‐10.0% were included. Analysis of covariance compared change from baseline to weeks 24 and 76 in HbA1c, body weight (BW) and systolic blood pressure (SBP) by respective baseline categories (HbA1c 90 kg, SBP 140 mmHg). Analyses were also conducted with a model using continuous covariates of cardio‐metabolic factors. Results In total, 637 patients (56.7% males; mean [SD] age 55.7 [9.9] years, HbA1c 7.9% [0.9%], BW 81.2 [18.8] kg, SBP 129.4 [14.6] mmHg) received one or more dose of either empagliflozin 10 mg (n = 217) or 25 mg (n = 213), or placebo (n = 207). At both time points, empagliflozin 10/25 mg versus placebo significantly (P < .0001) reduced HbA1c and BW, with greater reductions in HbA1c at higher baseline HbA1c (P interaction week 24/76 categorical and continuous models: .0290/.1431 and .0004/.0042, respectively) and in BW (P interaction .1340/.0012 and .0202/

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, HbA1c 5.9% [5.8–6.1%] [41.0 (39.9–43.2) mmol ⋅ mol−1]) 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 (P ≥ 0.28). However, insulin was lower in LV-HIIE (mean [95% CI] −44.4 [−23.7, −65.1] mU ⋅ L−1) and CME (−33.8 [−13.7, −53.9] mU ⋅ L−1) compared with CON. Insulin responses were greater in South Asians (interaction P = 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.

Aim To quantify the risk of cardiovascular disease (CVD) events, all-cause mortality and cardiovascular mortality in patients diagnosed with type 2 diabetes (T2D) and multimorbidity. Methods This retrospective study used English primary and secondary care data to identify 120 409 adults newly diagnosed with T2D during 2000-2018 with follow-up until death or 31 December 2018. Patients were classified according to the level and type of multimorbidity at T2D diagnosis, and adjusted hazard ratios (aHRs) were calculated for each outcome. Results In total, 66 977 (55.6%) patients had T2D only, 37 894 (31.5%) had one co-morbidity, 11 357 (9.4%) had two co-morbidities, 3186 (2.6%) patients had three co-morbidities and 995 (0.8%) patients had four or more co-morbidities. Co-morbidities were associated with increased aHRs for all outcomes. Compared with patients with T2D only, at 19 years after diagnosis of T2D the aHR for four or more co-morbidities was 2.57 (95% CI 2.45-2.69) for a CVD event, 1.73 (1.68-1.78) for all-cause mortality and 2.68 (2.52-2.85) for cardiovascular mortality. Also, 100 183 (83.2%) patients had no CVD co-morbidities, 16 874 (14.0%) patients had one CVD co-morbidity and 3352 (2.8%) patients had two or more co-morbidities. Compared with patients with no CVD co-morbidities, at 19 years after diagnosis of T2D the aHR for two or more CVD co-morbidities was 2.42 (2.35-2.49) for a CVD event, 1.44 (1.42-1.47) for all-cause mortality and 2.44 (2.35-2.54) for cardiovascular mortality. Conclusion In people with T2D, level of multimorbidity and, in particular, CVD multimorbidity increased the risk of subsequent CVD events, mortality and cardiovascular mortality.

Aims To (1) explore and verify differences in the plasma proteome of white European (WE) and South Asian (SA) adults with normal glycaemic control (NGC) or non-diabetic hyperglycaemia (NDH) and to (2) validate these findings using a separate WE and SA cohort at a high risk of NDH. Methods Mass spectrometry analysis was performed on fasted samples from 72 WE or SA men with NGC or NDH. These results were verified using specific biochemical assays and validated by repeating the analysis in an additional cohort of 30 WE and 30 SA adults. Proteomic results were analysed using independent samples t test and univariate analysis. The targeted assay results were analysed using generalised linear models with adjustment for appropriate covariates including age, BMI, fasting plasma glucose, high-density lipoprotein-cholesterol, triglycerides and sex. Results Only zinc-alpha-2-glycoprotein (ZAG) significantly differed between both ethnicities and glycaemic control groups. ZAG-specific biochemical assays verified the lower circulating ZAG in SAs (41.09 versus 37.07 (mg L−1); p = 0.014), but not the difference between NGC and NDH groups (p = 0.539). Validation of the ethnicity difference in a separate cohort confirmed that, after adjustment for covariates, ZAG was lower in SAs (p = 0.018). There was no association between ZAG and glycaemic control in the validation cohort. Conclusions Our analyses identified that ZAG is lower in SAs compared to WEs, but its difference between glycaemic control statuses was uncertain. Further research is needed to establish whether lower ZAG in SAs is associated with, or prognostic of, health outcomes, particularly regarding the risk of dysglycaemia.

This study compared initiation of insulin and other AHAs with canagliflozin versus placebo for participants with type 2 diabetes and a history/high risk of cardiovascular disease in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. After 1 year fewer participants treated with canagliflozin versus placebo initiated any AHA (7% vs 16%), insulin (3% vs 9%;) or any non-insulin AHA (5% vs 12%; p

Background Cardiovascular disease is responsible for 31% of all global deaths. Primary prevention strategies are needed to improve longer-term adherence to statins and healthy lifestyle behaviours to reduce risk in people at risk of cardiovascular disease. Methods Pragmatic randomised controlled trial recruited between May 2016 and March 2017 from primary care practices, England. Participants (n = 212) prescribed statins for primary prevention of cardiovascular disease with total cholesterol level ≥ 5 mmol/l were randomised: 105 to the intervention group and 107 to the control group, stratified by age and sex. The 3R intervention involved two facilitated, structured group education sessions focusing on medication adherence to statins, lifestyle behaviours and cardiovascular risk, with 44 weeks of medication reminders and motivational text messages and two supportive, coaching phone calls (at approximately 2 weeks and 6 months). The control group continued with usual clinical care. Both groups received a basic information leaflet. The primary outcome was medication adherence to statins objectively measured by a biochemical urine test. Self-reported adherence and practice prescription data provided additional measures. Secondary outcomes included cholesterol profile, blood pressure, anthropometric data, cardiovascular risk score, and self-reported lifestyle behaviours and psychological measures (health/medication beliefs, quality of life, health status). All outcomes were assessed at 12 months. Results Baseline adherence to statins was 47% (control) and 62% (intervention). No significant difference between the groups found for medication adherence to statins using either the urine test (OR 1.02, 95% CI 0.34 to 3.06, P = 0.968) or other measures. This may have been due to the higher than expected adherence levels at baseline. The adjusted mean difference between the groups (in favour of the intervention group) for diastolic blood pressure (− 4.28 mmHg (95% CI − 0.98 to − 1.58, P = 0.002)) and waist circumference (− 2.55 cm (95% CI − 4.55 to − 0.55, P = 0.012)). The intervention group also showed greater perceived control of treatment and more coherent understanding of the condition. Conclusions The 3R programme successfully led to longer-term improvements in important clinical lifestyle indicators but no improvement in medication adherence, raising questions about the suitability of such a broad, multiple risk factor approach for improving medication adherence for primary prevention of CVD. Trial registration International Standard Randomized Controlled Trial Number (ISRCTN16863160), March 11, 2006.

The increased risk of developing type 2 diabetes mellitus (T2DM) in women with a history of previous gestational diabetes mellitus (GDM) has been established and is well recognised. Post-partum screening for T2DM is essential to identify those at higher risk and allow for the implementation of preventative interventions. However, attendance rates for post-partum glucose screening in women with previous GDM remain substantially low, with only half of them attending screening. This review aimed to outline the National Institute for Health and Care Excellence (NICE) post-partum screening recommendations and compare them with the guidelines being used worldwide, provide information on post-partum screening uptake and possible determinants of uptake in the UK, and to briefly discuss both patient health implications and the financial burden associated with T2DM progression in the context of the National Health Service (NHS).

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%), 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.

Early initiated and long-term sustained intensive glucose control is associated with a significantly decreased risk of cardiovascular events and all-cause mortality, over and above the well-established decline in the risk of microvascular disease. Based on the recent cardiovascular outcome trial (CVOT) data, this review focuses on the various benefits of the newer medications with their positioning in the treatment algorithm and explores the place of the older medications in the management of type 2 diabetes mellitus (T2DM).We searched the literature for glucose-lowering therapies for patients with T2DM. We included CVOTs conducted for newer sulphonylureas, thiazolidinediones, insulin degludec, DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists.Selection of glucose-lowering therapy in the management of T2DM should be individualized and based on patient characteristics, associated comorbidities, patient preference, affordability and adherence to treatment. In view of the benefits seen in the CVOTs with SGLT2 inhibitors and GLP-1 receptor agonists, these newer classes should be the preferred choice in patients with/without established atherosclerotic cardiovascular disease and chronic kidney disease.

Primary care providers are well-positioned to help patients with type 2 diabetes achieve glycemic control while reducing their risks of serious complications such as atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease. Recent outcomes trials of glucagon-like peptide 1 receptor agonists and sodium– glucose cotransporter 2 inhibitors have revealed that these agents offer cardiorenal benefits beyond their glucose-lowering effects. The American Diabetes Association and the European Association for the Study of Diabetes now recommend a person-centered approach to type 2 diabetes treatment through which a patient’s multimorbidities, preferences, characteristics, and barriers are considered alongside A1C in individualizing the diabetes management plan. Here, we review the evidence supporting this guidance and describe how to implement the new holistic approach. Research has demonstrated the potential for offering a continuum of benefit from primary through tertiary prevention of microvascular and macrovascular disease while also achieving glycemic targets. The new outcomes-based guidelines provide a roadmap for integrating this newfound knowledge into clinical practice.

To systematically review the current literature investigating associations between zinc-alpha2-glycoprotein (ZAG) and dysglycaemia (including type 2 diabetes (T2DM), poly-cystic-ovary syndrome (PCOS), pre-diabetes or insulin resistance). This included relationships between ZAG and continuous measures of insulin and glucose. Additionally, we performed a meta-analysis to estimate the extent that ZAG differs between individuals with or without dysglycaemia; whilst examining the potential influence of adiposity. A systematic search was performed on four databases for studies on circulating ZAG concentrations in adult human populations, comparing healthy controls to individuals with dysglycaemia. Key characteristics, including the mean ZAG concentrations (mg∙L−1), and any correlational statistics between ZAG and continuous measures of glucose, glycated haemoglobin (HbA1c) or insulin were extracted. Meta-analyses were performed to compare metabolically healthy controls to cases, and on studies that compared controls and cases considered overweight or obese (body mass index (BMI) ≥25 kg.m2). 1575 papers were identified and 14 studies (16 cohorts) were considered eligible for inclusion. Circulating ZAG was lower in individuals with dysglycaemia compared to metabolically healthy controls (−4.14 [−8.17, −0.11] mg.L−1; I2 = 98.5%; p n = 332), the difference in circulating ZAG was no longer significant (−0.30 [−3.67, 3.07] mg. L−1; I2 = 28.0%; p = 0.225). These data suggest that ZAG may be implicated in dysglycaemia, although there was significant heterogeneity across different studies and the mediating effect of adiposity cannot be excluded. Therefore, more research is needed before robust conclusions can be drawn.

To evaluate the effects of the Diabetes Education and Self-Management for Ongoing and Newly Diagnosed (DESMOND) program on patient activation in adults living with type 2 diabetes (T2D).233 individuals attended a DESMOND program in 26 locations across regional Western Australia. Individuals completed the Patient Activation Measure (PAM) prior to and immediately after DESMOND participation.Patient Activation significantly increased by 9.7 points from pre to post DESMOND intervention (p 0.001, z = -7.94). Of all participants who exhibited an increase in patient activation, 87% (n = 142) experienced a clinically significant (5 point) increase. Post-DESMOND participation, an 86% reduction (from 6% -0.9%) in the proportion of participants scoring in the lowest PAM level (Level 1) was observed (p 0.01).DESMOND, a structured diabetes self-management education (DSME) program aimed at strengthening the role of people living with type 2 diabetes in self-managing their healthcare, significantly increased patient activation in a real-world setting.In line with international diabetes guidelines it is recommended that people living with T2D, particularly those with lower levels of activation, attend an evidence based DSME such as DESMOND to increase their capacity to effectively self-manage their condition.

The aim was to investigate how measurements of the lipidome differ according to the level and intensity of physical activity in a population at high risk of type 2 diabetes (T2DM). A targeted metabolomics platform provided quantitative molecular data on lipid species. Linear regression examined the associations between plasma lipid concentrations, particle size and time spent in objectively measured physical activity intensity domains, in increments of 500 counts per minute (cpm) (up to >4500 cpm (~>5.6METs)). Results are presented as % difference in the concentration (lower/higher) or particle size (smaller/larger) per 10 min of activity within each intensity. Five hundred and nine participants were included. Time spent in the lowest physical activity intensity domain (

IntroductionType 2 diabetes and cardiovascular disease are highly prevalent conditions, for which health education represents a significant component of management. A wide variety of health education formats are available and preferences of people with diabetes or cardiovascular disease for certain formats may vary between sociodemographic groups.MethodsA questionnaire was deployed to collect information about the influence of six sociodemographic factors of interest on the preference for health education format in type 2 diabetes and/or cardiovascular disease. Chi-squared tests were used to examine the distribution of preferences between groups. The characteristics of the population preferring the online format were then examined in more detail using logistic regression.ResultsResponses were received from 1559 participants. Overall the preferred modality was one to one learning from a doctor or nurse (67%). Age, gender, diagnosis and educational level all affected the preferences expressed. The characteristics showing most consistent and significant influence were age and educational level. Overall, 29% ranked the online modality highly (1 or 2). This group were more likely to be aged under 65 (p

OBJECTIVE To confirm the presence of subclinical cardiovascular dysfunction in working-age adults with type 2 diabetes (T2D) and determine whether this is improved by a low-energy meal replacement diet (MRP) or exercise training. RESEARCH DESIGN AND METHODS This article reports on a prospective, randomized, open-label, blinded end point trial with nested case-control study. Asymptomatic younger adults with T2D were randomized 1:1:1 to a 12-week intervention of 1) routine care, 2) supervised aerobic exercise training, or 3) a low-energy (∼810 kcal/day) MRP. Participants underwent echocardiography, cardiopulmonary exercise testing, and cardiac magnetic resonance (CMR) at baseline and 12 weeks. The primary outcome was change in left ventricular (LV) peak early diastolic strain rate (PEDSR) as measured by CMR. Healthy volunteers were enrolled for baseline case-control comparison. RESULTS Eighty-seven participants with T2D (age 51 ± 7 years, HbA1c 7.3 ± 1.1%) and 36 matched control participants were included. At baseline, those with T2D had evidence of diastolic dysfunction (PEDSR 1.01 ± 0.19 vs. 1.10 ± 0.16 s−1, P = 0.02) compared with control participants. Seventy-six participants with T2D completed the trial (30 routine care, 22 exercise, and 24 MRP). The MRP arm lost 13 kg in weight and had improved blood pressure, glycemia, LV mass/volume, and aortic stiffness. The exercise arm had negligible weight loss but increased exercise capacity. PEDSR increased in the exercise arm versus routine care (β = 0.132, P = 0.002) but did not improve with the MRP (β = 0.016, P = 0.731). CONCLUSIONS In asymptomatic working-age adults with T2D, exercise training improved diastolic function. Despite beneficial effects of weight loss on glycemic control, concentric LV remodeling, and aortic stiffness, a low-energy MRP did not improve diastolic function.

Purpose To identify predictors of favorable changes to postprandial insulin and glucose levels in response to interrupting prolonged sitting time with standing or light-intensity physical activity. Methods Data were combined from four similarly designed randomized acute cross-over trials (n = 129; body mass index [BMI] range, 19.6–44.6 kg·m−2; South Asian = 31.0%; dysglycemia = 27.1%). Treatments included: prolonged sitting (6.5 h) or prolonged sitting broken-up with either standing or light-intensity physical activity (5 min every 30 min). Time-averaged postprandial responses for insulin and glucose were calculated for each treatment (mean ± 95% confidence interval). Mutually adjusted interaction terms were used to examine whether anthropometric (BMI), demographic (age, sex, ethnicity [white European vs South Asian]) and a cardiometabolic variable (Homeostatic Model Assessment of Insulin Resistance)-modified responses. Results Postprandial insulin and glucose were reduced when individuals interrupted prolonged sitting with bouts of light physical activity, but not with standing. Reductions in time-averaged postprandial insulin were more pronounced if individuals were South Asian compared with white European (−18.9 mU·L−1 [−23.5%] vs −8.2 mU·L−1 [−9.3%]), female compared with male (−15.0 mU·L−1 [−21.2%] vs −12.1 mU·L−1 [−17.6%]) or had a BMI ≥27.2 kg·m−2 (−20.9 mU·L−1 [−22.9%] vs −8.7 mU·L−1 [−18.2%]). Similarly, being female (−0.4 mmol·L−1 [−0.6 mmol·L−1, −0.2 mmol·L−1], −6.8% vs –0.1 mmol·L−1 [−0.3 mmol·L−1, 1 mmol·L−1], −1.7%) or having a BMI ≥27.2 kg·m−2 (−0.4 mmol·L−1 [−0.6 mmol·L−1, −0.2 mmol·L−1], −6.7% vs –0.2 mmol·L−1 [−0.4 mmol·L−1, 0.0 mmol·L−1], −3.4%) modified the postprandial glucose response. No significant interactions were found for Homeostatic Model Assessment of Insulin Resistance or age. Conclusions Being female, South Asian, or having a higher BMI, all predicted greater reductions in postprandial insulin, whereas being female and having a higher BMI predicted greater reductions in postprandial glucose when sitting was interrupted with light physical activity. These results could help to guide personalized interventions in high-risk participants for whom breaking prolonged sitting time with light activity may yield the greatest therapeutic potential.

To establish whether associations between sedentary behavior and cardiometabolic health differ when assessed by thigh-worn and waist-worn accelerometry.Participants were recruited from several areas in the United Kingdom. Sedentary behavior was assessed using the activPAL worn on the thigh and ActiGraph worn on the waist. Average total (TST), prolonged (bouts ≥30 min; PST) and breaks (BST) in sedentary time were calculated. Cardiometabolic health markers included: adiposity (body fat) and surrogate markers of adiposity ((waist circumference, body mass index [BMI]), lipids (total, low density lipoprotein, and high-density lipoprotein [HDL] cholesterol, triglycerides), blood pressure, and glucose (fasting, 2 h and glycated hemoglobin A1c). A clustered cardiometabolic risk score was calculated. Linear regression analysis examined the associations with cardiometabolic health.There were 1457 participants (mean age [± standard deviation], 59.38 ± 11.85 yr; 51.7% male; mean BMI, 30.19 ± 5.59 kg·m) included in the analyses. ActivPAL and ActiGraph sedentary variables were moderately correlated (0.416-0.511, P0.01); however, all variables were significantly different from each other (P0.05). Consistency was observed across devices in the direction and magnitude of associations of TST and PST with adiposity, surrogate markers of adiposity, HDL, triglycerides, and cardiometabolic risk score and for BST with adiposity, surrogate markers of adiposity, and cardiometabolic risk. Differences across devices were observed in associations of TST and PST with diastolic blood pressure, for TST with 2-h glucose and for BST with HDL. No other associations were observed for any other health marker for either device.Results suggest that associations with cardiometabolic health are largely comparable across the two common assessments of sedentary behavior but some small differences may exist for certain health markers.

Background and Aims Intake of red and processed meat has been associated with a higher risk of morbidity and mortality; it is unknown whether these associations are modified by overall physical health. This study examined the associations of red and processed meat consumption with all–cause, cardiovascular, and cancer mortality and investigated whether markers of physical function modified the associations. Methods and Results This observational cohort study used UK Biobank data derived from 419 075 participants free from cancer and cardiovascular disease. Cox models assessed the association of red and processed meat consumption (obtained from a baseline food frequency questionnaire) with mortality, adjusted for potential confounders. Objectively measured handgrip strength and self-reported walking pace were used as interaction terms. The median age was 57 (interquartile range, 49–63) years and 54.9% were women. Over 7 years of follow–up, 8586 all–cause, 1660 cardiovascular, and 4812 cancer deaths occurred. Each additional serving per week of red and processed meat was associated with a hazard ratio (HR) of 1.037 (95% CI: 1.028-1.047) for all–cause; 1.030 (1.009-1.051) for cardiovascular; and 1.029 (1.016-1.042) for cancer mortality. The association of red and processed meat consumption was modified by walking pace, with brisk walkers having the lowest risk per additional serving for all–cause and cancer mortality (HR 1.025; 1.006-1.045 and 1.015; 0.990-1.040, respectively); no interaction was observed for handgrip strength. Conclusion The known risk of mortality associated with red and processed meat consumption may be lower in those with high physical function.

Aims Psychological comorbidity, such as depression and/or diabetes-specific emotional distress (DSD), is highly prevalent in people with type 2 diabetes (T2DM) and associated with poorer treatment outcomes. While treatments for depression are well established, interventions specifically designed for DSD are sparse. The aim of this study was to determine interventions that successfully address DSD and HbA1c in people with T2DM. Methods Seven databases were searched to identify potentially relevant studies. Eligible studies were selected and appraised independently by two reviewers. Multiple meta-analyses and meta-regression analyses were performed to synthesise the data; the primary analyses determined the effect of interventions on DSD, with secondary analyses assessing the effect on HbA1c. Results Thirty-two studies (n = 5206) provided sufficient DSD data, of which 23 (n = 3818) reported data for HbA1c. Meta-analyses demonstrated that interventions significantly reduced DSD (p = 0.034) and HbA1c (p = 0.006) compared to controls, although subgroup meta-analyses and meta-regression to explore specific intervention characteristics that might mediate this effect yielded non-significant findings. Conclusions The findings demonstrate that existing interventions successfully reduce DSD and HbA1c in people with T2DM. While promising, deductions should be interpreted tentatively, highlighting a stark need for further focused exploration of how best to treat psychological comorbidity in people with T2DM.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are well established in clinical practice for the treatment of type 2 diabetes, and are approved and recommended for weight management in overweight or obesity. Gastrointestinal side effects are well known as the most common adverse effects of these agents and represent a potential barrier for use, particularly at higher doses. Drawing on both published evidence and our collective clinical experience, we aim to guide practitioners through managing these side effects with a view to optimizing therapeutic outcomes with GLP-1RAs.

BackgroundTargeted self-management programmes may improve health and increase physical activity (PA) in people with multimorbidity.AimTo investigate the impact of a structured, theoretically driven, self-management group education programme on habitual PA levels in people with multimorbidity.Design and settingIndividually randomised controlled trial with 12-month follow-up, involving nine primary care practices in Leicestershire, UK.MethodIn total, 353 adults with multimorbidity (age 67.8 years [±9 years], 161 male sex) were randomised to intervention (n= 180) or control (n= 173) groups. Intervention participants were invited to attend four group-based self-management sessions, centred primarily on increasing PA, and received motivational text-message support. The primary outcome measure was change in overall volume (time and intensity) of daily PA at 12 months, as measured by the GENEActiv wrist-worn accelerometer device.ResultsAt baseline, the total sample achieved 22 min of moderate–vigorous intensity PA per day (mean/participant). At 12 months, in the complete-case analysis, a reduction in daily mean PA volume was seen in the intervention group relative to control (−0.80 milligravity [mg]; 95% confidence interval [CI] = −1.57 to −0.03;P= 0.04). Reductions were also seen in the intervention group in time spent in moderate–vigorous PA (−3.86 min per day; 95% CI= −6.70 to −1.03;P= 0.008) and time spent at an intensity equivalent to a slow walk (−4.66 min per day; 95% CI = −8.82 to −0.51;P= 0.028). However, the per-protocol analysis (excluding participants who did not attend at least one education session) found no between-group differences in overall daily PA at 12 months (−0.65 mg; 95% CI = −1.46 to 0.15;P= 0.11).ConclusionThe self-management programme elicited a slight reduction in PA levels in people with multimorbidity. Future research should identify and target subgroups of those with multimorbidity in greatest need of PA promotion in order to maximise potential capacity for benefit, and also focus on refining the intervention in order to increase efficacy in increasing PA.

Background The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107). Findings We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9–6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40–59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity. Interpretation We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care. Funding UK Research and Innovation and National Institute for Health Research.

Objective To assess trends in primary and specialist care consultation rates and average length of consultation by cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), or cardiometabolic multimorbidity exposure status. Methods Observational, retrospective cohort study used linked Clinical Practice Research Datalink primary care data from 01/01/2000 to 31/12/2018 to assess consultation rates in 141,328 adults with newly diagnosed T2DM, with or without CVD. Patients who entered the study with either a diagnosis of T2DM or CVD and later developed the second condition during the study are classified as the cardiometabolic multimorbidity group. Face to face primary and specialist care consultations, with either a nurse or general practitioner, were assessed over time in subjects with T2DM, CVD, or cardiometabolic multimorbidity. Changes in the average length of consultation in each group were investigated. Results 696,255 (mean 4.9 years [95% CI, 2.02–7.66]) person years of follow up time, there were 10,221,798 primary and specialist care consultations. The crude rate of primary and specialist care consultations in patients with cardiometabolic multimorbidity (N = 11,881) was 18.5 (95% CI, 18.47–18.55) per person years, 13.5 (13.50, 13.52) in patients with T2DM only (N = 83,094) and 13.2 (13.18, 13.21) in those with CVD (N = 57,974). Patients with cardiometabolic multimorbidity had 28% (IRR 1.28; 95% CI: 1.27, 1.31) more consultations than those with only T2DM. Patients with cardiometabolic multimorbidity had primary care consultation rates decrease by 50.1% compared to a 45.0% decrease in consultations for those with T2DM from 2000 to 2018. Specialist care consultation rates in both groups increased from 2003 to 2018 by 33.3% and 54.4% in patients with cardiometabolic multimorbidity and T2DM, respectively. For patients with T2DM the average consultation duration increased by 36.0%, in patients with CVD it increased by 74.3%, and in those with cardiometabolic multimorbidity it increased by 37.3%. Conclusions Annual primary care consultation rates for individuals with T2DM, CVD, or cardiometabolic multimorbidity have fallen since 2000, while specialist care consultations and average consultation length have both increased. Individuals with cardiometabolic multimorbidity have significantly more consultations than individuals with T2DM or CVD alone. Service redesign of health care delivery needs to be considered for people with cardiometabolic multimorbidity to reduce the burden and health care costs.

Funder: National Institute for Health Research; doi: http://dx.doi.org/10.13039/501100000272; Grant(s): NIHR Applied Research Collaboration East Midlands (ARC EM), NIHR Leicester Biomedical Research Centre, Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014), Background: Pre-existing comorbidities have been linked to SARS-CoV-2 infection but evidence is sparse on the importance and pattern of multimorbidity (2 or more conditions) and severity of infection indicated by hospitalisation or mortality. We aimed to use a multimorbidity index developed specifically for COVID-19 to investigate the association between multimorbidity and risk of severe SARS-CoV-2 infection. Methods: We used data from the UK Biobank linked to laboratory confirmed test results for SARS-CoV-2 infection and mortality data from Public Health England between March 16 and July 26, 2020. By reviewing the current literature on COVID-19 we derived a multimorbidity index including: (1) angina; (2) asthma; (3) atrial fibrillation; (4) cancer; (5) chronic kidney disease; (6) chronic obstructive pulmonary disease; (7) diabetes mellitus; (8) heart failure; (9) hypertension; (10) myocardial infarction; (11) peripheral vascular disease; (12) stroke. Adjusted logistic regression models were used to assess the association between multimorbidity and risk of severe SARS-CoV-2 infection (hospitalisation/death). Potential effect modifiers of the association were assessed: age, sex, ethnicity, deprivation, smoking status, body mass index, air pollution, 25‐hydroxyvitamin D, cardiorespiratory fitness, high sensitivity C-reactive protein. Results: Among 360,283 participants, the median age was 68 [range 48–85] years, most were White (94.5%), and 1706 had severe SARS-CoV-2 infection. The prevalence of multimorbidity was more than double in those with severe SARS-CoV-2 infection (25%) compared to those without (11%), and clusters of several multimorbidities were more common in those with severe SARS-CoV-2 infection. The most common clusters with severe SARS-CoV-2 infection were stroke with hypertension (79% of those with stroke had hypertension); diabetes and hypertension (72%); and chronic kidney disease and hypertension (68%). Multimorbidity was independently associated with a greater risk of severe SARS-CoV-2 infection (adjusted odds ratio 1.91 [95% confidence interval 1.70, 2.15] compared to no multimorbidity). The risk remained consistent across potential effect modifiers, except for greater risk among older age. The highest risk of severe infection was strongly evidenced in those with CKD and diabetes (4.93 [95% CI 3.36, 7.22]). Conclusion: The multimorbidity index may help identify individuals at higher risk for severe COVID-19 outcomes and provide guidance for tailoring effective treatment.

Introduction Left atrial (LA) strain has been shown to be an independent predictor of cardiovascular events in many conditions and superior to conventional measures of LA function (LA volumes and emptying fraction). The effects of low-energy diet or exercise on cardiovascular function in younger adults with type 2 diabetes (DIASTOLIC) study has previously demonstrated an improvement in left ventricle peak early diastolic strain rate in response to aerobic exercise in patients with type-2 diabetes (T2D). However, the effect of lifestyle intervention on LA function, assessed by cardiac magnetic resonance (CMR) imaging, is unknown. Methods The DIASTOLIC study was a prospective, randomised, open-label, blind endpoint trial, that randomised 90 obese participants with T2D (aged 18–65 years) to a 12-week intervention of: (i) routine care, (ii) aerobic exercise training, or (iii) low energy (≈810kcal/day) meal replacement plan (MRP). CMR was performed at baseline and week-12. Images were analysed using Medis v3.1. LA strain (LAS) was assessed using Feature Tracking (QStrain v2.0), corresponding to LA reservoir (LAS-r), conduit (LAS-cd), and booster pump (LAS-bp) using 4- and 2-chamber standard steady-state free precession cine images, and average values calculated. LA emptying fraction (LAEF) was calculated using biplane area-length method (QMass v8.1) for total, passive and active EF. Results 73 participants with T2D completed the trial and had analysable LA images (28 routine care, 22 exercise and 23 MRP). There was no significant change in CMR measured standard LA volumetric function (LAV/LAEF) and echocardiogram measured LV filling pressures (E/e') in any groups. The routine care arm showed no significant change in body mass index (BMI) or LAS (see Table). In the MRP group, there were significant reductions in BMI (4.8 kg/m2), mean systolic blood pressure (SBP) (13mmHg), and a significant increase in LAS-r and LAS-bp (29.9±7.0 to 32.3±7.0,p=0.036 and 14.6±5.3 to 17.2±3.7,p=0.034). The exercise arm showed a small reduction in BMI (0.8kg/m2), with no significant change in BP or LAS. Conclusion There was significant improvement in LAS post-lifestyle intervention in young adults with T2D, despite no change in volumetric measurements. MRP led to weight loss and improved SBP, with associated improved LA filling and contraction. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute for Health Research (NIHR) a career development fellowship.

Throughout history, up to the early part of the 20th century, diabetes has been a devastating disorder, particularly when diagnosed in childhood when it was usually fatal. Consequently, the successful pancreatic extraction of insulin in 1921 was a miraculous, life-changing advance. In this review, the truly transformative effect that insulin has had on the lives of people with type 1 diabetes and on those with type 2 diabetes who are also dependent on insulin is described, from the time of its first successful use to the present day. We have highlighted in turn how each of the many facets of improvements over the last century, from advancements in the properties of insulin and its formulations to the evolution of different methods of delivery, have led to continued improvement in clinical outcomes, through the use of illustrative stories from history and from our own clinical experiences. This review concludes with a brief look at the current challenges and where the next century of technological innovation in insulin therapy may take us.

Funder: UKRI Science and Technology Facilities Council, OBJECTIVE: To quantify the association between accelerometer-assessed physical activity and coronavirus disease 2019 (COVID-19) outcomes. METHODS: Data from 82,253 UK Biobank participants with accelerometer data (measured 2013-2015), complete covariate data, and linked COVID-19 data from March 16, 2020, to March 16, 2021, were included. Two outcomes were investigated: severe COVID-19 (positive test result from in-hospital setting or COVID-19 as primary cause of death) and nonsevere COVID-19 (positive test result from community setting). Logistic regressions were used to assess associations with moderate to vigorous physical activity (MVPA), total activity, and intensity gradient. A higher intensity gradient indicates a higher proportion of vigorous activity. RESULTS: Average MVPA was 48.1 (32.7) min/d. Physical activity was associated with lower odds of severe COVID-19 (adjusted odds ratio per standard deviation increase: MVPA, 0.75 [95% CI, 0.67 to 0.85]; total, 0.83 [0.74 to 0.92]; intensity, 0.77 [0.70 to 0.86]), with stronger associations in women (MVPA, 0.63 [0.52 to 0.77]; total, 0.76 [0.64 to 0.90]; intensity, 0.63 [0.53 to 0.74]) than in men (MVPA, 0.84 [0.73 to 0.97]; total, 0.88 [0.77 to 1.01]; intensity, 0.88 [0.77 to 1.00]). In contrast, when mutually adjusted, total activity was associated with higher odds of a nonsevere infection (1.10 [1.04 to 1.16]), whereas the intensity gradient was associated with lower odds (0.91 [0.86 to 0.97]). CONCLUSION: Odds of severe COVID-19 were approximately 25% lower per standard deviation (∼30 min/d) MVPA. A greater proportion of vigorous activity was associated with lower odds of severe and nonsevere infections. The association between total activity and higher odds of a nonsevere infection may be through greater community engagement and thus more exposure to the virus. Results support calls for public health messaging highlighting the potential of MVPA for reducing the odds of severe COVID-19.

ObjectivesWalking pace is a strong marker of functional and health status. We investigated whether walking pace is also associated with leucocyte telomere length (LTL), which is causally associated with several diseases and has been proposed as a marker of biological age.MethodsWe used baseline data from UK Biobank participants recruited from March-2006 to July-2010. Walking pace was self-reported as slow, steady/average, or brisk. Accelerometer-assessed measures of total physical activity and intensity were included to support interpretation of walking pace data. LTL was measured by qPCR assay. Bi-directional Mendelian randomization (MR) analyses were undertaken to inform likely causal directions.ResultsThe analysed cohort comprised 405,981 adults (54% women) with mean age of 56.5 years (SD, 8.1) and body mass index 27.2 kg/m2 (SD, 4.7). Steady/average and brisk walkers had significantly longer LTL compared with slow walkers, with a Z-standardised LTL difference of 0.066 (0.053-0.078) and 0.101 (0.088-0.113), respectively. Associations remained but were attenuated following full covariate adjustment: 0.038 (0.025-0.051) and 0.058 (0.045-0.072), respectively. Accelerometer data (n=86,002) demonstrated a non-linear association between LTL and habitual movement intensity, but not total activity. MR analysis supported a causal association of walking pace on LTL, with an increase in Z-standardised LTL of 0.192 (0.077, 0.306) for each difference in walking pace category. No evidence of a causal association was observed for LTL on walking pace.ConclusionFaster walking pace may be causally associated with longer LTL, which could explain some of the beneficial effects of brisk walking on health status.

BackgroundGlobally, there are estimated 425 million people with type 2 diabetes (T2D) with 80% from low-middle income countries (LMIC). Diabetes self-management education (DSME) programmes are a vital and core component of the treatment pathway for T2D. Despite LMIC being disproportionally affected by T2D, there are no DSME available that meet international diabetes federation criterion.MethodsThe aims were to test the feasibility of delivering a proven effective and cost-effective approach used in a UK population in two urban settings in Malawi and Mozambique by; (1) developing a culturally, contextually and linguistically adapted DSME, the EXTending availability of self-management structured EducatioN programmes for people with type 2 Diabetes in low-to-middle income countries (EXTEND) programme; (2) using a mixed-method approach to evaluate the delivery of training and the EXTEND programme to patients with T2D.ResultsTwelve healthcare professionals were trained. Ninety-eight participants received the DSME. Retention was high (100% in Mozambique and 94% in Malawi). At 6 months HbA1c (−0.9%), cholesterol (−0.3 mmol/L), blood pressure (−5.9 mm Hg systolic and −6.1 mm Hg diastolic) improved in addition to indicators of well-being (problem areas in diabetes and self-efficacy in diabetes).ConclusionIt is feasible to deliver and evaluate the effectiveness of a culturally, contextually and linguistically adapted EXTEND programme in two LMIC. The DSME was acceptable with positive biomedical and psychological outcomes but requires formal testing with cost-effectiveness. Challenges exist in scaling up such an approach in health systems that do not have resources to address the challenge of diabetes.