Comparison of intramyocellular lipid metabolism in patients with diabetes and male athletes.

Despite opposing insulin sensitivity and cardiometabolic risk, both athletes and patients with type 2 diabetes have increased skeletal myocyte fat storage: the so-called "athlete's paradox". In a parallel non-randomised, non-blinded trial (NCT03065140), we characterised and compared the skeletal myocyte lipid signature of 29 male endurance athletes and 30 patients with diabetes after undergoing deconditioning or endurance training respectively. The primary outcomes were to assess intramyocellular lipid storage of the vastus lateralis in both cohorts and the secondary outcomes were to examine saturated and unsaturated intramyocellular lipid pool turnover. We show that athletes have higher intramyocellular fat saturation with very high palmitate kinetics, which is attenuated by deconditioning. In contrast, type 2 diabetes patients have higher unsaturated intramyocellular fat and blunted palmitate and linoleate kinetics but after endurance training, all were realigned with those of deconditioned athletes. Improved basal insulin sensitivity was further associated with better serum cholesterol/triglycerides, glycaemic control, physical performance, enhanced post insulin receptor pathway signalling and metabolic sensing. We conclude that insulin-resistant, maladapted intramyocellular lipid storage and turnover in patients with type 2 diabetes show reversibility after endurance training through increased contributions of the saturated intramyocellular fatty acid pools. Clinical Trial Registration: NCT03065140: Muscle Fat Compartments and Turnover as Determinant of Insulin Sensitivity (MISTY).

Ongoing burden and recent trends in severe hospitalised hypoglycaemia events in people with type 1 and type 2 diabetes in Scotland: A nationwide cohort study 2016-2022.

AIMS: We examined severe hospitalised hypoglycaemia (SHH) rates in people with type 1 and type 2 diabetes in Scotland during 2016-2022, stratifying by sociodemographics. METHODS: Using the Scottish National diabetes register (SCI-Diabetes), we identified people with type 1 and type 2 diabetes alive anytime during 2016-2022. SHH events were determined through linkage to hospital admission and death registry data. We calculated annual SHH rates overall and by age, sex, and socioeconomic status. Summary estimates of time and stratum effects were obtained by fitting adjusted generalised additive models using R package mgcv. RESULTS: Rates for those under 20 with type 1 diabetes reached their minimum at the 2020-2021 transition, 30% below the study period average. A gradual decline over time also occurred among 20-49-year-olds with type 1 diabetes. Overall, females had 15% higher rates than males with type 2 diabetes (rate ratio 1.15, 95% CI 1.08-1.22). People in the most versus least deprived quintile experienced 2.58 times higher rates (95% CI 2.27-2.93) in type 1 diabetes and 2.33 times higher (95% CI 2.08-2.62) in type 2 diabetes. CONCLUSIONS: Despite advances in care, SHH remains a significant problem in diabetes. Future efforts must address the large socioeconomic disparities in SHH risks.

Morning exercise and pre-breakfast metformin interact to reduce glycaemia in people with type 2 diabetes: a randomized crossover trial.

Exercise is recommended in the treatment of type 2 diabetes and can improve insulin sensitivity. However, previous evidence suggests that exercise at different times of the day in people with type 2 diabetes may have opposing outcomes on glycaemia. Metformin is the most commonly prescribed initial pharmacological intervention in type 2 diabetes, and may alter adaptions to exercise. It is unknown if there is an interaction between metformin and diurnal exercise outcomes. We aimed to investigate glycaemic outcomes of moderate intensity morning vs. evening exercise in people with type 2 diabetes being prescribed metformin monotherapy. In this study, nine males and nine females with type 2 diabetes undergoing metformin monotherapy (age 61 ± 8.2 years, mean ± SD) completed a 16-week crossover trial including 2-week baseline recording, 6 weeks randomly assigned to a morning exercise (07.00-10.00 h) or evening exercise (16.00-19.00 h) and a 2-week wash-out period. Exercise arms consisted of 30 min of walking at 70% of estimated max heart rate every other day. Glucose levels were measured with continuous glucose monitors and activity measured by wrist-worn monitors. Food-intake was recorded by 4-day food diaries during baseline, first and last 2 weeks of each exercise arm. There was no difference in exercise intensity, total caloric intake or total physical activity between morning and evening arms. As primary outcomes, acute (24 h) glucose area under the curve (AUC), was lower (P = 0.02) after acute morning exercise (180.6 ± 68.4 mmol/l) compared to baseline (210.3 ± 76.7 mmol/l); and there were no differences identified for glucose (mmol/l) between baseline, morning and evening exercise at any specific time point when data were analysed with two-way ANOVA. As secondary outcomes, acute glucose AUC was significantly lower (P = 0.01) in participants taking metformin before breakfast (152.5 ± 29.95 mmol/l) compared with participants taking metformin after breakfast (227.2 ± 61.51 mmol/l) only during the morning exercise arm; and during weeks 5-6 of the exercise protocol, glucose AUC was significantly lower (P = 0.04) for participants taking metformin before breakfast (168.8 ± 15.8 mmol/l), rather than after breakfast (224.5 ± 52.0 mmol/l), only during morning exercise. Our data reveal morning moderate exercise acutely lowers glucose levels in people with type 2 diabetes being prescribed metformin. This difference appears to be driven by individuals that consumed metformin prior to breakfast rather than after breakfast. This beneficial effect upon glucose levels of combined morning exercise and pre-breakfast metformin persisted through the final 2 weeks of the trial. Our findings suggest that morning moderate intensity exercise combined with pre-breakfast metformin intake may benefit the management of glycaemia in people with type 2 diabetes. KEY POINTS: Morning moderate exercise acutely lowers glucose levels in people with type 2 diabetes being prescribed metformin. This difference appears to be driven by individuals that consumed metformin prior to breakfast rather than after breakfast. Morning exercise combined with pre-breakfast metformin persistently reduced glucose compared to morning exercise combined with post-breakfast metformin through the final week (week 6) of the intervention. Our study suggests it may be possible to make simple changes to the time that people with type 2 diabetes take metformin and perform exercise to improve their blood glucose.

Creating a SNOMED CT reference set for common endocrine disorders based on routine clinic correspondence.

BACKGROUND: Routine clinical coding of clinical outcomes in outpatient consultations still lags behind the coding of episodes of inpatient care. Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) offers an opportunity for standardised coding of key clinical information. Identifying the most commonly required SNOMED terms and grouping these into a reference set will aid future adoption in routine clinical care. OBJECTIVE: To create a common endocrinology reference set to standardise the coding for outcomes of outpatient endocrine consultations, using a semi-automated extraction of information from existing clinical correspondence. METHODS: Retrospective review of data from an adult tertiary outpatient endocrine clinic between 2018 and 2019. A total of 1870 patients from postcodes within two regional areas of NHS Grampian (Aberdeen City and Aberdeenshire) attended the clinic. Following consultation, an automated script extracted each problem statement which was manually coded using the 'disorder' concepts from SNOMED CT (UK edition). RESULTS: The review identified 298 relevant endocrine diagnoses, 99 findings and 142 procedures. There were a total of 88 (29.5%) commonly seen endocrine conditions (e.g., Graves' disease, anterior hypopituitarism and Addison's disease) and 210 (70.5%) less commonly seen endocrine conditions. Subsequently, consultant endocrinologists completed a survey regarding the common endocrine conditions; 28 conditions have 100% agreement, 25 have 90%-99% agreement, 31 have 50%-89% agreement and 4 have less than 59% agreement (which were excluded). CONCLUSION: Automated text parsing of structured endocrine correspondence allowed the creation of a SNOMED CT reference set for common endocrine disorders. This will facilitate funding and planning of service provision in endocrinology by allowing more accurate characterisation of the patient cohorts needing specialist endocrine care.

Effect of the dual sodium-glucose co-transporter-1 and -2 inhibitor sotagliflozin on renal outcomes in type 1 diabetes and type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials.

AIM: To investigate the renal safety profile of sotagliflozin, a novel sodium-glucose co-transporter-1 and -2 inhibitor, in patients with type 1 diabetes and type 2 diabetes, with or without renal impairment, as well as its efficacy in decreasing the risk of further renal events, with an emphasis on those with previous renal impairment. METHODS: Embase, Medline, CENTRAL and Scopus were searched from their inception until 24 April 2023 for randomized controlled trials that reported estimated glomerular filtration rate (eGFR), urinary albumin excretion or composite renal events (CRE). The Cochrane risk of bias 2 tool was used. Mean difference, relative risk (RR) and 95% confidence intervals were estimated (PROSPERO: CRD42023425583). RESULTS: Fourteen studies were included in this review (n = 17 574 participants; intervention n = 9312, control n = 8262). The median follow-up was 24.5 (Q1 = 15.25, Q3 = 28) months. Four studies recruited participants with renal impairment; baseline eGFR ranged from 23.8 to 50.5 mL/min/1.73m2 . The change in eGFR for studies (n = 6) with a follow-up of 52 weeks or longer was -1.23 (-1.45, -1.01) mL/min/1.73m2 . Sotagliflozin did not significantly alter urinary albumin excretion. No change was observed in the risk of CRE (n = 6 studies; RR = 0.82 [0.61, 1.12]), including in participants with renal impairment. High risk of bias was a limitation of this review. CONCLUSIONS: Sotagliflozin did not adversely affect renal function or change the risk of key renal outcomes, including for participants with pre-existing renal impairment. Therefore, sotagliflozin was safe; however, further research is needed to determine its efficacy in reducing the risk of diabetic kidney disease.

Myeloid PTP1B deficiency protects against atherosclerosis by improving cholesterol homeostasis through an AMPK-dependent mechanism.

OBJECTIVE: Atherosclerosis is a chronic inflammatory process induced by the influx and entrapment of excess lipoproteins into the intima media of arteries. Previously, our lab demonstrated that systemic PTP1B inhibition protects against atherosclerosis in preclinical LDLR-/- models. Similarly, it was shown that myeloid-specific PTP1B ablation decreases plaque formation and ameliorates dyslipidaemia in the ApoE-/- model of atherosclerosis. We hypothesized that the relevant improvements in dyslipidaemia following modification of PTP1B activation may either result from changes in hepatic cholesterol biosynthesis and/or increased uptake and degradation by liver-resident macrophages. We examined this in animal models and patients with coronary artery disease. METHODS: In this study, we determined the cholesterol-lowering effect of myeloid-PTP1B deletion in mice fed a high-fat high-cholesterol diet and examined effects on total cholesterol levels and lipoprotein profiles. We also determined the effects of PTP1B inhibition to oxLDL-C challenge on foam cell formation and cholesterol efflux in human monocytes/macrophages. RESULTS: We present evidence that myeloid-PTP1B deficiency significantly increases the affinity of Kupffer cells for ApoB containing lipoproteins, in an IL10-dependent manner. We also demonstrate that PTP1B inhibitor, MSI-1436, treatment decreased foam cell formation in Thp1-derived macrophages and increased macrophage cholesterol efflux to HDL in an AMPK-dependent manner. We present evidence of three novel and distinct mechanisms regulated by PTP1B: an increase in cholesterol efflux from foam cells, decreased uptake of lipoproteins into intra-lesion macrophages in vitro and a decrease of circulating LDL-C and VLDL-C in vivo. CONCLUSIONS: Overall, these results suggest that myeloid-PTP1B inhibition has atheroprotective effects through improved cholesterol handling in atherosclerotic lesions, as well as increased reverse cholesterol transport. Trial registration Research registry, researchregistry 3235. Registered 07 November 2017, https://www.researchregistry.com/browse-the-registry#home/registrationdetails/5a01d0fce7e1904e93e0aac5/ .

Compound Scaling Encoder-Decoder (CoSED) Network for Diabetic Retinopathy Related Bio-marker Detection.

Biomedical image segmentation plays an important role in Diabetic Retinopathy (DR)-related biomarker detection. DR is an ocular disease that affects the retina in people with diabetes and could lead to visual impairment if management measures are not taken in a timely manner. In DR screening programs, the presence and severity of DR are identified and classified based on various microvascular lesions detected by qualified ophthalmic screeners. Such a detection process is time-consuming and error-prone, given the small size of the microvascular lesions and the volume of images, especially with the increasing prevalence of diabetes. Automated image processing using deep learning methods is recognized as a promising approach to support diabetic retinopathy screening. In this paper, we propose a novel compound scaling encoder-decoder network architecture to improve the accuracy and running efficiency of microvascular lesion segmentation. In the encoder phase, we develop a lightweight encoder to speed up the training process, where the encoder network is scaled up in depth, width, and resolution dimensions. In the decoder phase, an attention mechanism is introduced to yield higher accuracy. Specifically, we employ Concurrent Spatial and Channel Squeeze and Channel Excitation (scSE) blocks to fully utilise both spatial and channel-wise information. Additionally, a compound loss function is incorporated with transfer learning to handle the problem of imbalanced data and further improve performance. To assess performance, our method is evaluated on two large-scale lesion segmentation datasets: DDR and FGADR datasets. Experimental results demonstrate the superiority of our method compared to other competent methods. Our codes are available at https://github.com/DeweiYi/CoSED-Net.

The role of ROX index-based intubation in COVID-19 pneumonia: a cross-sectional comparison and retrospective survival analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) patients with acute respiratory failure who experience delayed initiation of invasive mechanical ventilation have poor outcomes. The lack of objective measures to define the timing of intubation is an area of concern. We investigated the effect of timing of intubation based on respiratory rate-oxygenation (ROX) index on the outcomes of COVID-19 pneumonia. METHODS: This was a retrospective cross-sectional study performed in a tertiary care teaching hospital in Kerala, India. Patients with COVID-19 pneumonia who were intubated were grouped into early intubation (within 12 hours of ROX index <4.88) or delayed intubation (12 hours or more hours after ROX <4.88). RESULTS: A total of 58 patients was included in the study after exclusions. Among them, 20 patients were intubated early, and 38 patients were intubated 12 hours after ROX index <4.88. The mean age of the study population was 57±14 years, and 55.0% of the patients were male; diabetes mellitus (48.3%) and hypertension (50.0%) were the most common comorbidities. The early intubation group had 88.2% successful extubation, while only 11.8% of the delayed group had successful extubation (P<0.001). Survival was also significantly more frequent in the early intubation group. CONCLUSIONS: Early intubation within 12 hours of ROX index <4.88 was associated with improved extubation and survival in patients with COVID-19 pneumonia.

Type 1 diabetes incidence in Scotland between 2006 and 2019.

AIMS: To describe type 1 diabetes incidence in Scotland between 2006 and 2019. METHODS: Repeated annual cross-sectional studies of type 1 diabetes incidence were conducted. Incident cases were identified from the Scottish Care Information-Diabetes Collaboration (SCI-DC), a population-based register of people with diagnosed diabetes derived from primary and secondary care data. Mid-year population estimates for Scotland were used as the denominator to calculate annual incidence with stratification by age and sex. Joinpoint regression was used to investigate whether incidence changed during the study period. Age and sex-specific type 1 diabetes incidence over the whole time period was estimated by quintile of the Scottish Index of Multiple Deprivation (SIMD), an area-based measure, in which Q1 and Q5 denote the most and least deprived fifths of the population, respectively, with quasi-Poisson regression used to compare incidence for Q5 compared to Q1. RESULTS: The median (IQR) age of the study population of 14,564 individuals with incident type 1 diabetes was 24.1 (12.3-42.4) years, 56% were men, 23% were in Q1 and 16% were in Q5. Incidence of T1DM was higher in men than women overall (at around 22 and 17 per 100,000, respectively) and in under 15 year olds (approximately 40 per 100,000 in both sexes) than other age groups and was similar across the study period in all strata. There was an inverse association between socio-economic status and type 1 diabetes incidence for 15-29, 30-49 and 50+ year olds [incidence rate ratio (IRR) for Q5 compared to Q1; IRR (95% CI) 0.52 (0.47-0.58), 0.68 (0.61-0.76) and 0.53(0.46-0.61), respectively] but not for under 15 year olds [1.02 (0.92-1.12)]. CONCLUSION: Incidence of type 1 diabetes varies by age, sex and socio-economic status and has remained approximately stable from 2006 to 2019 in Scotland.

Cohort profile: the Scottish Diabetes Research Network national diabetes cohort - a population-based cohort of people with diabetes in Scotland.

PURPOSE: The Scottish Diabetes Research Network (SDRN)-diabetes research platform was established to combine disparate electronic health record data into research-ready linked datasets for diabetes research in Scotland. The resultant cohort, 'The SDRN-National Diabetes Dataset (SDRN-NDS)', has many uses, for example, understanding healthcare burden and socioeconomic trends in disease incidence and prevalence, observational pharmacoepidemiology studies and building prediction tools to support clinical decision making. PARTICIPANTS: We estimate that >99% of those diagnosed with diabetes nationwide are captured into the research platform. Between 2006 and mid-2020, the cohort comprised 472 648 people alive with diabetes at any point in whom there were 4 million person-years of follow-up. Of the cohort, 88.1% had type 2 diabetes, 8.8% type 1 diabetes and 3.1% had other types (eg, secondary diabetes). Data are captured from all key clinical encounters for diabetes-related care, including diabetes clinic, primary care and podiatry and comprise clinical history and measurements with linkage to blood results, microbiology, prescribed and dispensed drug and devices, retinopathy screening, outpatient, day case and inpatient episodes, birth outcomes, cancer registry, renal registry and causes of death. FINDINGS TO DATE: There have been >50 publications using the SDRN-NDS. Examples of recent key findings include analysis of the incidence and relative risks for COVID-19 infection, drug safety of insulin glargine and SGLT2 inhibitors, life expectancy estimates, evaluation of the impact of flash monitors on glycaemic control and diabetic ketoacidosis and time trend analysis showing that diabetic ketoacidosis (DKA) remains a major cause of death under age 50 years. The findings have been used to guide national diabetes strategy and influence national and international guidelines. FUTURE PLANS: The comprehensive SDRN-NDS will continue to be used in future studies of diabetes epidemiology in the Scottish population. It will continue to be updated at least annually, with new data sources linked as they become available.

User-Centered Design of A Novel Risk Prediction Behavior Change Tool Augmented With an Artificial Intelligence Engine (MyDiabetesIQ): A Sociotechnical Systems Approach.

BACKGROUND: Diabetes and its complications account for 10% of annual health care spending in the United Kingdom. Digital health care interventions (DHIs) can provide scalable care, fostering diabetes self-management and reducing the risk of complications. Tailorability (providing personalized interventions) and usability are key to DHI engagement/effectiveness. User-centered design of DHIs (aligning features to end users' needs) can generate more usable interventions, avoiding unintended consequences and improving user engagement. OBJECTIVE: MyDiabetesIQ (MDIQ) is an artificial intelligence engine intended to predict users' diabetes complications risk. It will underpin a user interface in which users will alter lifestyle parameters to see the impact on their future risks. MDIQ will link to an existing DHI, My Diabetes My Way (MDMW). We describe the user-centered design of the user interface of MDIQ as informed by human factors engineering. METHODS: Current users of MDMW were invited to take part in focus groups to gather their insights about users being shown their likelihood of developing diabetes-related complications and any risks they perceived from using MDIQ. Findings from focus groups informed the development of a prototype MDIQ interface, which was then user-tested through the "think aloud" method, in which users speak aloud about their thoughts/impressions while performing prescribed tasks. Focus group and think aloud transcripts were analyzed thematically, using a combination of inductive and deductive analysis. For think aloud data, a sociotechnical model was used as a framework for thematic analysis. RESULTS: Focus group participants (n=8) felt that some users could become anxious when shown their future complications risks. They highlighted the importance of easy navigation, jargon avoidance, and the use of positive/encouraging language. User testing of the prototype site through think aloud sessions (n=7) highlighted several usability issues. Issues included confusing visual cues and confusion over whether user-updated information fed back to health care teams. Some issues could be compounded for users with limited digital skills. Results from the focus groups and think aloud workshops were used in the development of a live MDIQ platform. CONCLUSIONS: Acting on the input of end users at each iterative stage of a digital tool's development can help to prioritize users throughout the design process, ensuring the alignment of DHI features with user needs. The use of the sociotechnical framework encouraged the consideration of interactions between different sociotechnical dimensions in finding solutions to issues, for example, avoiding the exclusion of users with limited digital skills. Based on user feedback, the tool could scaffold good goal setting, allowing users to balance their palatable future complications risk against acceptable lifestyle changes. Optimal control of diabetes relies heavily on self-management. Tools such as MDMW/ MDIQ can offer personalized support for self-management alongside access to users' electronic health records, potentially helping to delay or reduce long-term complications, thereby providing significant reductions in health care costs.

Flash monitor initiation is associated with improvements in HbA1c levels and DKA rates among people with type 1 diabetes in Scotland: a retrospective nationwide observational study.

AIMS/HYPOTHESIS: We assessed the real-world effect of flash monitor (FM) usage on HbA1c levels and diabetic ketoacidosis (DKA) and severe hospitalised hypoglycaemia (SHH) rates among people with type 1 diabetes in Scotland and across sociodemographic strata within this population. METHODS: This study was retrospective, observational and registry based. Using the national diabetes registry, 14,682 individuals using an FM at any point between 2014 and mid-2020 were identified. Within-person change from baseline in HbA1c following FM initiation was modelled using linear mixed models accounting for within-person pre-exposure trajectory. DKA and SHH events were captured through linkage to hospital admission and mortality data. The difference in DKA and SHH rates between FM-exposed and -unexposed person-time was assessed among users, using generalised linear mixed models with a Poisson likelihood. In a sensitivity analysis, we tested whether changes in these outcomes were seen in an age-, sex- and baseline HbA1c-matched sample of non-users over the same time period. RESULTS: Prevalence of ever-FM use was 45.9% by mid-2020, with large variations by age and socioeconomic status: 64.3% among children aged <13 years vs 32.7% among those aged ≥65 years; and 54.4% vs 36.2% in the least-deprived vs most-deprived quintile. Overall, the median (IQR) within-person change in HbA1c in the year following FM initiation was -2.5 (-9.0, 2.5) mmol/mol (-0.2 [-0.8, 0.2]%). The change varied widely by pre-usage HbA1c: -15.5 (-31.0, -4.0) mmol/mol (-1.4 [-2.8, -0.4]%) in those with HbA1c > 84 mmol/mol [9.8%] and 1.0 (-2.0, 5.5) mmol/mol (0.1 [-0.2, 0.5]%) in those with HbA1c < 54 mmol/mol (7.1%); the corresponding estimated fold change (95% CI) was 0.77 (0.76, 0.78) and 1.08 (1.07, 1.09). Significant reductions in HbA1c were found in all age bands, sexes and socioeconomic strata, and regardless of prior/current pump use, completion of a diabetes education programme or early FM adoption. Variation between the strata of these factors beyond that driven by differing HbA1c at baseline was slight. No change in HbA1c in matched non-users was observed in the same time period (median [IQR] within-person change = 0.5 [-5.0, 5.5] mmol/mol [0.0 (-0.5, 0.5)%]). DKA rates decreased after FM initiation overall and in all strata apart from the adolescents. Estimated overall reduction in DKA event rates (rate ratio) was 0.59 [95% credible interval (CrI) 0.53, 0.64]) after FM vs before FM initiation, accounting for pre-exposure trend. Finally, among those at higher risk for SHH, estimated reduction in event rates was rate ratio 0.25 (95%CrI 0.20, 0.32) after FM vs before FM initiation. CONCLUSIONS/INTERPRETATION: FM initiation is associated with clinically important reductions in HbA1c and striking reduction in DKA rate. Increasing uptake among the socioeconomically disadvantaged offers considerable potential for tightening the current socioeconomic disparities in glycaemia-related outcomes.

Foot Ulcer and Risk of Lower Limb Amputation or Death in People With Diabetes: A National Population-Based Retrospective Cohort Study.

OBJECTIVE: To describe incidence of foot ulceration and amputation-free survival associated with foot ulceration status in a national population-based cohort study of people with diabetes. RESEARCH DESIGN AND METHODS: The study population included 233,459 people with diabetes who were alive in Scotland on 1 January 2012 identified from the national population-based register (national prevalence 4.9%). Characteristics of patients identified from linked hospital and mortality records during follow-up to the end of November 2017 were compared by outcome. Cox regression was used to assess the association between history of foot ulcer and amputation-free survival. RESULTS: The population included 23,395 people with type 1 diabetes and 210,064 people with type 2 diabetes. In total there were 13,093 (5.6%) people who had a previous foot ulceration, 9,023 people who developed a first ulcer, 48,995 who died, and 2,866 who underwent minor or major amputation during follow-up. Overall incidence of first-time foot ulcers was 7.8 per 1,000 person-years (95% CI7.6-7.9) and 11.2 (11.0-11.4) for any ulcer. Risk factors for reduced amputation-free survival included social deprivation, mental illness, and being underweight in addition to conventional cardiovascular risk factors. Adjusted hazard ratios (95% CI) were 2.09 (1.89-2.31) for type 1 diabetes and 1.65 (1.60-1.70) for type 2 diabetes. CONCLUSIONS: The overall incidence of foot ulceration in a population-based study of people with diabetes was 11.2 per 1,000 person-years. Foot ulceration is associated with lower amputation-free survival rate, a potential measure of effectiveness of care among people with diabetes. Mental illness and social deprivation are also highlighted as risk factors.

Marked improvements in glycaemic outcomes following insulin pump therapy initiation in people with type 1 diabetes: a nationwide observational study in Scotland.

AIMS/HYPOTHESIS: Our aim was to assess the use of continuous subcutaneous insulin infusion (CSII) in people with type 1 diabetes in Scotland and its association with glycaemic control, as measured by HbA1c levels, frequency of diabetic ketoacidosis (DKA) and severe hospitalised hypoglycaemia (SHH), overall and stratified by baseline HbA1c. METHODS: We included 4684 individuals with type 1 diabetes from the national Scottish register, who commenced CSII between 2004 and 2019. We presented crude within-person differences from baseline HbA1c over time since initiation, crude DKA and SHH event-rates pre-/post-CSII exposure. We then used mixed models to assess the significance of CSII exposure, taking into account: (1) the diffuse nature of the intervention (i.e. structured education often precedes initiation); (2) repeated within-person measurements; and (3) background time-trends occurring pre-intervention. RESULTS: HbA1c decreased after CSII initiation, with a median within-person change of -5.5 mmol/mol (IQR -12.0, 0.0) (-0.5% [IQR -1.1, 0.0]). Within-person changes were most substantial in those with the highest baseline HbA1c, with median -21.0 mmol/mol (-30.0, -11.0) (-1.9% [-2.7, -1.0]) change in those with a baseline >84 mmol/mol (9.8%) within a year of exposure, that was sustained: -19.0 mmol/mol (-27.6, -6.5) (-1.7% [-2.5, -0.6]) at ≥5 years. Statistical significance and magnitude of change were supported by the mixed models results. The crude DKA event-rate was significantly lower in post-CSII person-time compared with pre-CSII person-time: 49.6 events (95% CI 46.3, 53.1) per 1000 person-years vs 67.9 (64.1, 71.9); rate ratio from Bayesian mixed models adjusting for pre-exposure trend: 0.61 (95% credible interval [CrI] 0.47, 0.77; posterior probability of reduction pp = 1.00). The crude overall SHH event-rate in post-CSII vs pre-CSII person-time was also lower: 17.8 events (95% CI 15.8, 19.9) per 1000 person-years post-exposure vs 25.8 (23.5, 28.3) pre-exposure; rate ratio from Bayesian mixed models adjusting for pre-exposure trend: 0.67 (95% CrI 0.45, 1.01; pp = 0.97). CONCLUSIONS/INTERPRETATION: CSII therapy was associated with marked falls in HbA1c especially in those with high baseline HbA1c. CSII was independently associated with reduced DKA and SHH rates. CSII appears to be an effective option for intensive insulin therapy in people with diabetes for improving suboptimal glycaemic control.

Risks of and risk factors for COVID-19 disease in people with diabetes: a cohort study of the total population of Scotland.

BACKGROUND: We aimed to ascertain the cumulative risk of fatal or critical care unit-treated COVID-19 in people with diabetes and compare it with that of people without diabetes, and to investigate risk factors for and build a cross-validated predictive model of fatal or critical care unit-treated COVID-19 among people with diabetes. METHODS: In this cohort study, we captured the data encompassing the first wave of the pandemic in Scotland, from March 1, 2020, when the first case was identified, to July 31, 2020, when infection rates had dropped sufficiently that shielding measures were officially terminated. The participants were the total population of Scotland, including all people with diabetes who were alive 3 weeks before the start of the pandemic in Scotland (estimated Feb 7, 2020). We ascertained how many people developed fatal or critical care unit-treated COVID-19 in this period from the Electronic Communication of Surveillance in Scotland database (on virology), the RAPID database of daily hospitalisations, the Scottish Morbidity Records-01 of hospital discharges, the National Records of Scotland death registrations data, and the Scottish Intensive Care Society and Audit Group database (on critical care). Among people with fatal or critical care unit-treated COVID-19, diabetes status was ascertained by linkage to the national diabetes register, Scottish Care Information Diabetes. We compared the cumulative incidence of fatal or critical care unit-treated COVID-19 in people with and without diabetes using logistic regression. For people with diabetes, we obtained data on potential risk factors for fatal or critical care unit-treated COVID-19 from the national diabetes register and other linked health administrative databases. We tested the association of these factors with fatal or critical care unit-treated COVID-19 in people with diabetes, and constructed a prediction model using stepwise regression and 20-fold cross-validation. FINDINGS: Of the total Scottish population on March 1, 2020 (n=5 463 300), the population with diabetes was 319 349 (5·8%), 1082 (0·3%) of whom developed fatal or critical care unit-treated COVID-19 by July 31, 2020, of whom 972 (89·8%) were aged 60 years or older. In the population without diabetes, 4081 (0·1%) of 5 143 951 people developed fatal or critical care unit-treated COVID-19. As of July 31, the overall odds ratio (OR) for diabetes, adjusted for age and sex, was 1·395 (95% CI 1·304-1·494; p<0·0001, compared with the risk in those without diabetes. The OR was 2·396 (1·815-3·163; p<0·0001) in type 1 diabetes and 1·369 (1·276-1·468; p<0·0001) in type 2 diabetes. Among people with diabetes, adjusted for age, sex, and diabetes duration and type, those who developed fatal or critical care unit-treated COVID-19 were more likely to be male, live in residential care or a more deprived area, have a COVID-19 risk condition, retinopathy, reduced renal function, or worse glycaemic control, have had a diabetic ketoacidosis or hypoglycaemia hospitalisation in the past 5 years, be on more anti-diabetic and other medication (all p<0·0001), and have been a smoker (p=0·0011). The cross-validated predictive model of fatal or critical care unit-treated COVID-19 in people with diabetes had a C-statistic of 0·85 (0·83-0·86). INTERPRETATION: Overall risks of fatal or critical care unit-treated COVID-19 were substantially elevated in those with type 1 and type 2 diabetes compared with the background population. The risk of fatal or critical care unit-treated COVID-19, and therefore the need for special protective measures, varies widely among those with diabetes but can be predicted reasonably well using previous clinical history. FUNDING: None.

Prescribing Paradigm Shift? Applying the 2019 European Society of Cardiology-Led Guidelines on Diabetes, Prediabetes, and Cardiovascular Disease to Assess Eligibility for Sodium-Glucose Cotransporter 2 Inhibitors or Glucagon-Like Peptide 1 Receptor Agonists as First-Line Monotherapy (or Add-on to Metformin Monotherapy) in Type 2 Diabetes in Scotland.

OBJECTIVE: In 2019, the European Society of Cardiology led and released new guidelines for diabetes cardiovascular risk management, reflecting recent evidence of cardiovascular disease (CVD) reduction with sodium-glucose cotransporter 2 inhibitors (SGLT-2is) and some glucagon-like peptide 1 receptor agonists (GLP-1RAs) in type 2 diabetes (T2D). A key recommendation is that all those with T2D who are (antihyperglycemic) drug naïve or on metformin monotherapy should be CVD risk stratified and an SGLT-2i or a GLP-1RA initiated in all those at high or very high risk, irrespective of glycated hemoglobin. We assessed the impact of these guidelines in Scotland were they introduced as is. RESEARCH DESIGN AND METHODS: Using a nationwide diabetes register in Scotland, we did a cross-sectional analysis, using variables in our register for risk stratification at 1 January 2019. We were conservative in our definitions, assuming the absence of a risk factor where data were not available. The risk classifications were applied to people who were drug naïve or on metformin monotherapy and the anticipated prescribing change calculated. RESULTS: Of the 265,774 people with T2D in Scotland, 53,194 (20.0% of those with T2D) were drug naïve, and 56,906 (21.4%) were on metformin monotherapy. Of these, 74.5% and 72.4%, respectively, were estimated as at least high risk given the guideline risk definitions. CONCLUSIONS: Thus, 80,830 (30.4%) of all those with T2D (n = 265,774) would start one of these drug classes according to table 7 and figure 3 of the guideline. The sizeable impact on drug budgets, enhanced clinical monitoring, and the trade-off with reduced CVD-related health care costs will need careful consideration.

Time trends in deaths before age 50 years in people with type 1 diabetes: a nationwide analysis from Scotland 2004-2017.

AIMS/HYPOTHESIS: We aimed to examine whether crude mortality and mortality relative to the general population below 50 years of age have improved in recent years in those with type 1 diabetes. METHODS: Individuals with type 1 diabetes aged below 50 and at least 1 year old at any time between 2004 and 2017 in Scotland were identified using the national register. Death data were obtained by linkage to Scottish national death registrations. Indirect age standardisation was used to calculate sex-specific standardised mortality ratios (SMRs). Poisson regression was used to test for calendar-time effects as incidence rate ratios (IRRs). RESULTS: There were 1138 deaths in 251,143 person-years among 27,935 people with type 1 diabetes. There was a significant decline in mortality rate over time (IRR for calendar year 0.983 [95% CI 0.967, 0.998], p = 0.03), but the SMR remained approximately stable at 3.1 and 3.6 in men and 4.09 and 4.16 in women for 2004 and 2017, respectively. Diabetic ketoacidosis or coma (DKAoC) accounted for 22% of deaths and the rate did not decline significantly (IRR 0.975 [95% CI 0.94, 1.011], p = 0.168); 79.3% of DKAoC deaths occurred out of hospital. Circulatory diseases accounted for 27% of deaths and did decline significantly (IRR 0.946 [95% CI 0.914, 0.979], p = 0.002). CONCLUSIONS/INTERPRETATION: Absolute mortality has fallen, but the relative impact of type 1 diabetes on mortality below 50 years has not improved. There is scope to improve prevention of premature circulatory diseases and DKAoC and to develop more effective strategies for enabling people with type 1 diabetes to avoid clinically significant hyper- or hypoglycaemia. Graphical abstract.

Use of personalised risk-based screening schedules to optimise workload and sojourn time in screening programmes for diabetic retinopathy: A retrospective cohort study.

BACKGROUND: National guidelines in most countries set screening intervals for diabetic retinopathy (DR) that are insufficiently informed by contemporary incidence rates. This has unspecified implications for interval disease risks (IDs) of referable DR, disparities in ID between groups or individuals, time spent in referable state before screening (sojourn time), and workload. We explored the effect of various screening schedules on these outcomes and developed an open-access interactive policy tool informed by contemporary DR incidence rates. METHODS AND FINDINGS: Scottish Diabetic Retinopathy Screening Programme data from 1 January 2007 to 31 December 2016 were linked to diabetes registry data. This yielded 128,606 screening examinations in people with type 1 diabetes (T1D) and 1,384,360 examinations in people with type 2 diabetes (T2D). Among those with T1D, 47% of those without and 44% of those with referable DR were female, mean diabetes duration was 21 and 23 years, respectively, and mean age was 26 and 24 years, respectively. Among those with T2D, 44% of those without and 42% of those with referable DR were female, mean diabetes duration was 9 and 14 years, respectively, and mean age was 58 and 52 years, respectively. Individual probability of developing referable DR was estimated using a generalised linear model and was used to calculate the intervals needed to achieve various IDs across prior grade strata, or at the individual level, and the resultant workload and sojourn time. The current policy in Scotland-screening people with no or mild disease annually and moderate disease every 6 months-yielded large differences in ID by prior grade (13.2%, 3.6%, and 0.6% annually for moderate, mild, and no prior DR strata, respectively, in T1D) and diabetes type (2.4% in T1D and 0.6% in T2D overall). Maintaining these overall risks but equalising risk across prior grade strata would require extremely short intervals in those with moderate DR (1-2 months) and very long intervals in those with no prior DR (35-47 months), with little change in workload or average sojourn time. Changing to intervals of 12, 9, and 3 months in T1D and to 24, 9, and 3 months in T2D for no, mild, and moderate DR strata, respectively, would substantially reduce disparity in ID across strata and between diabetes types whilst reducing workload by 26% and increasing sojourn time by 2.3 months. Including clinical risk factor data gave a small but significant increment in prediction of referable DR beyond grade (increase in C-statistic of 0.013 in T1D and 0.016 in T2D, both p < 0.001). However, using this model to derive personalised intervals did not have substantial workload or sojourn time benefits over stratum-specific intervals. The main limitation is that the results are pertinent only to countries that share broadly similar rates of retinal disease and risk factor distributions to Scotland. CONCLUSIONS: Changing current policies could reduce disparities in ID and achieve substantial reductions in workload within the range of IDs likely to be deemed acceptable. Our tool should facilitate more rational policy setting for screening.

Performance of Cardiovascular Disease Risk Scores in People Diagnosed With Type 2 Diabetes: External Validation Using Data From the National Scottish Diabetes Register.

OBJECTIVE: To evaluate the performance of five cardiovascular disease (CVD) risk scores developed in diabetes populations and compare their performance to QRISK2. RESEARCH DESIGN AND METHODS: A cohort of people diagnosed with type 2 diabetes between 2004 and 2016 was identified from the Scottish national diabetes register. CVD events were identified using linked hospital and death records. Five-year risk of CVD was estimated using each of QRISK2, ADVANCE (Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation), Cardiovascular Health Study (CHS), New Zealand Diabetes Cohort Study (NZ DCS), Fremantle Diabetes Study, and Swedish National Diabetes Register (NDR) risk scores. Discrimination and calibration were assessed using the Harrell C statistic and calibration plots, respectively. RESULTS: The external validation cohort consisted of 181,399 people with type 2 diabetes and no history of CVD. There were 14,081 incident CVD events within 5 years of follow-up. The 5-year observed risk of CVD was 9.7% (95% CI 9.6, 9.9). C statistics varied between 0.66 and 0.67 for all risk scores. QRISK2 overestimated risk, classifying 87% to be at high risk for developing CVD within 5 years; ADVANCE underestimated risk, and the Swedish NDR risk score calibrated well to observed risk. CONCLUSIONS: None of the risk scores performed well among people with newly diagnosed type 2 diabetes. Using these risk scores to predict 5-year CVD risk in this population may not be appropriate.

Diabetes and pregnancy: national trends over a 15 year period.

AIMS/HYPOTHESIS: We aimed to examine time trends in national perinatal outcomes in pregnancies complicated by pre-existing type 1 or type 2 diabetes. METHODS: We analysed episode-level data on all obstetric inpatient delivery events (live or stillbirth) between 1 April 1998 and 31 March 2013 (n = 813,921) using the Scottish Morbidity Record (SMR02). Pregnancies to mothers with type 1 (n = 3229) and type 2 (n = 1452) diabetes were identified from the national diabetes database (Scottish Care Information-Diabetes), and perinatal outcomes were compared among women with type 1 diabetes, type 2 diabetes and those without diabetes. RESULTS: The number of pregnancies complicated by diabetes increased significantly, by 44% in type 1 diabetes and 90% in type 2 diabetes, across the 15 years examined, to rates of 1 in 210 and 1 in 504 deliveries, respectively. Compared with women without diabetes, delivery occurred 2.6 weeks earlier (type 1 diabetes 36.7 ± 2.3 weeks) and 2 weeks earlier (type 2 diabetes 37.3 ± 2.4 weeks), respectively, showing significant reductions for both type 1 (from 36.7 weeks to 36.4 weeks, p = 0.03) and type 2 (from 38.0 weeks to 37.2 weeks, p < 0.001) diabetes across the time period. The proportions of preterm delivery were markedly increased in women with diabetes (35.3% type 1 diabetes, 21.8% type 2 diabetes, 6.1% without diabetes; p < 0.0001), and these proportions increased with time for both groups (p < 0.005). Proportions of elective Caesarean sections (29.4% type 1 diabetes, 30.5% type 2 diabetes, 9.6% without diabetes) and emergency Caesarean sections (38.3% type 1 diabetes, 29.1% type 2 diabetes, 14.6% without diabetes) were greatly increased in women with diabetes and increased over time except for stable rates of emergency Caesarean section in type 1 diabetes. Gestational age-, sex- and parity-adjusted z score for birthweight (1.33 ± 1.34; p < 0.001) were higher in type 1 diabetes and increased over time from 1.22 to 1.47 (p < 0.001). Birthweight was also increased in type 2 diabetes (0.94 ± 1.34; p < 0.001) but did not alter with time. There were 65 perinatal deaths in offspring of mothers with type 1 diabetes and 39 to mothers with type 2 diabetes, representing perinatal mortality rates of 20.1 (95% CI 14.7, 24.3) and 26.9 (16.7, 32.9) per 1000 births, respectively, and rates 3.1 and 4.2 times, respectively, those observed in the non-diabetic population (p < 0.001). Stillbirth rates in type 1 and type 2 diabetes were 4.0-fold and 5.1-fold that in the non-diabetic population (p < 0.001). Perinatal mortality and stillbirth rates showed no significant fall over time despite small falls in the rates for the non-diabetic population. CONCLUSIONS/INTERPRETATION: Women with diabetes are receiving increased intervention in pregnancy (earlier delivery, increased Caesarean section rates), but despite this, higher birthweights are being recorded. Improvements in rates of stillbirth seen in the general population are not being reflected in changes in stillbirth or perinatal mortality in our population with diabetes.