Use Of Glucose-lowering Medications Research Articles

#100 Hospital readmissions for fluid overload among individuals with diabetes mellitus

Abstract Background and Aims Hospital readmissions due to recurrent fluid overload in diabetes can be avoided with evidence-based interventions. To identify at-risk individuals, we evaluated the incidence and risk factors associated with fluid overload-related hospital readmissions and developed risk prediction models for readmissions for fluid overload in people with diabetes. Method Single-centre retrospective cohort study of 1531 adults with diabetes and hospitalized in Singapore General Hospital for fluid overload, congestive heart failure, pulmonary edema and generalized edema between 2015 and 2017. Patients were included if they had diabetes mellitus identified by the SingHealth Diabetes Registry according to diagnosis codes, laboratory results and/or the use of glucose-lowering medication and had follow up visits, but excluded if their estimated glomerular filtration rate (eGFR) <15 ml/min/1.73 m2. Baseline data on demographics, comorbidities, biochemistry and medication use during admission were retrieved from electronic medical records up till 30 December 2018. The outcomes were fluid overload- related readmissions within 30 days and 90 days of discharge of the index hospitalization. Multivariable Cox proportional-hazards regression analysis was performed with inclusion of covariates with p≤0.10 on univariate analysis. Multivariable regression models developed were compared with the LACE index with net reclassification index (NRI). Results Among 1531 patients, median age was 73 (IQR 64, 81) and readmissions for fluid overload within 30 days and 90 days occurred in 131 (8.6%) and 264 (17.2%) patients, respectively. Individuals with 30- or 90-day readmissions were more likely to have prior hospitalization for fluid overload and more frequent ED visits within 6 months before the index hospitalization, cardiovascular disease, hypertension, and required high-dose intravenous furosemide during the index hospitalization, or current smoker. Clinical and clinico-psychosocial models for 30- and 90-day readmissions for fluid overload were developed (Table 1). The clinical and clinico-psychosocial models showed better discrimination and calibration than LACE index for predicting 30- and 90-day readmissions for fluid overload. The NRIs for clinical models were i. 30-day readmissions: +22.1%, ii. 90-day readmissions: +27.9% respectively, while the NRIs for clinico-psychosocial models were i. 30-day readmissions: +22.4%, ii. 90-day readmissions: +28.9% respectively (Fig. 1). Conclusion Patients with diabetes who are at-risk of readmission for fluid overload can be identified for targeted interventions to reduce preventable hospitalizations.

#2852 Iron status and incident diabetes in kidney transplant recipients

Abstract Background and Aims Kidney transplant recipients (KTR) are prone to develop post-transplant diabetes (PTD). Iron plays a role in glucose homeostasis and patients with iron overload have a high prevalence of diabetes. Since iron overload can also occur in KTR, we investigated whether levels of ferritin are associated with incident PTD in KTR. Method This is a prospective observational cohort study of adult KTR ≥1 year after transplantation of the Transplantlines Insulin Resistance and Inflammation Biobank and Cohort study. Cox regression analyses were applied to study the association of serum ferritin with incident PTD (fasting plasma glucose ≥126 mg/dL, or nonfasting plasma glucose ≥200 mg/dL combined with diabetes symptoms, or use of glucose-lowering medication). Models were adjusted for age, sex, body mass index, C-reactive protein (CRP), diabetes risk factors, transplantation factors, and immunosuppressive drugs. To explore potential clinical cut-offs of ferritin levels from which the risk of PTD might increase, categories of ferritin (<100, 100-300, 300-500, and >500 µg/L) were used in subsequent analysis. Results We included 399 KTR (age 51 [IQR, 41-59 years], 54% males, and at a median of 6.1 [3.0-12.1] years after transplantation) without diabetes at baseline. During a median follow-up of 9.7 [7.6-10.3] years, 45 KTR (11%) developed PTD. In multivariable Cox regression analyses, serum ferritin levels were significantly associated with incident PTD independent of adjustment for potential confounders (Table 1, hazard ratio (HR) per 50 µg/L, 1.12; 95% CI 1.05-1.18; P = 0.0002). Furthermore, in analysis with ferritin categories, we identified that KTR with ferritin >500 µg/L (n = 38) had a significantly higher chance of PTD compared to KTR with ferritin between 100-300 µg /L (Fig. 1, HR, 3.66; 95% CI 1.37-9.77; P = 0.01). KTR with ferritin levels <100 and between 300-500 µg/L had a similar risk of PTD compared to KTR with ferritin levels between 100-300 µg/L. Conclusion Ferritin levels are associated with PTD in KTR, independent of other known diabetes risk factors, including inflammation. KTR with ferritin levels above 500 µg/L appear particularly prone to develop PTD. Further investigation should determine the underlying mechanisms and consequences of these findings with respect to target goals of ferritin levels after kidney transplantation.

Trends in the Use of Medications for Secondary Ischemic Stroke Prevention in Denmark, 2005-2021.

Understanding trends in the use of medications for secondary stroke prevention is crucial for identifying areas for improvement in stroke care. We examined the use of lipid-lowering, antihypertensive, glucose-lowering, oral anticoagulant, and antiplatelet medications after ischemic stroke hospitalization, from 2005 to 2021. Using nationwide registries in Denmark, we identified a cohort of patients discharged from hospital with a first-time or recurrent ischemic stroke (N = 150,744). Stratified by calendar year, we ascertained the 180-day probability of filling a prescription for the abovementioned medications after discharge. We further assessed factors associated with medication use. From 2005 to 2021, lipid-lowering medication use increased from 58.3% to 82.0%; atorvastatin use rose from 2.1% to 64.8% and simvastatin use decreased from 55.7% to 8.6%. Antihypertensive medication use remained stable, at approximately 89%, and various antihypertensive classes were used comparably. Glucose-lowering medication use increased from 71.5% in 2005 to 84.1% in 2021, driven primarily by an increase in metformin use (from 28.0% to 59.5%). Use of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors continually increased (from 1.7% to 17.5% and from 0.5% to 17.3%, respectively) between 2015 and 2021. Anticoagulant medication use rose from 45.9% in 2005 to 87.0% in 2021, primarily because of increased use of direct oral anticoagulant medications starting around 2010 and a decline in warfarin use. Antiplatelet use remained consistently high, at approximately 95%. Trends were consistent across subgroups of interest; however, overall medication use was lower in older patients (65 years and older), patients with severe stroke, and patients with neurologic and psychiatric comorbidities. Despite increasing trends in the use of 3 of 5 medication classes, the overall use of lipid-lowering, glucose-lowering, and oral anticoagulant medications was somewhat lower than expected according to clinical guidelines, particularly among older patients with more severe stroke and other comorbidities. The relatively low use in these subgroups may signify appropriate clinical decision making in consideration of frequent contraindications and reduced life expectancy or highlight potential areas of improvement for the care of patients with recent ischemic stroke.

Glycemic control during TB treatment among Filipinos: The Starting Anti-Tuberculosis Treatment Cohort Study.

Poor TB treatment outcomes are observed in patients with type 2 diabetes mellitus (DM) comorbidity and glycemic control throughout treatment may play a role. The objective of this study was to investigate glycemic control longitudinally among Filipino adults undergoing TB treatment using mixed-effects linear and logistic regression. Analyses were conducted in 188 DM-TB patients out of 901 enrolled in the Starting Anti-TB Treatment (St-ATT) cohort, with a median baseline glycosylated hemoglobin (HbA1c) of 8.2% (range 4.5-13.3%). Previous versus new DM diagnosis was associated with higher mean HbA1c (worse glycemic control) during treatment, with a smaller effect amongst those with central obesity (coefficient 0.80, 95% confidence interval [CI] 0.26, 1.57, P = 0.043) than amongst those without central obesity (coefficient 3.48, 95% CI 2.16, 4.80, P<0.001). In those with a new DM diagnosis, central obesity was associated with higher blood glucose (coefficient 1.62, 95% CI 0.72, 2.53, P = 0.009). Of 177 participants with ≥2 HbA1c results, 40% had uncontrolled glycemia (≥2 HbA1c results ≥8%). Of 165 participants with ≥3 HbA1c results, 29.9% had consistently-controlled glycemia, 15.3% had initially-uncontrolled glycemia, and 18.6% had consistently-uncontrolled glycemia. Previous versus new DM diagnosis and glucose-lowering medication use versus no use were associated with having uncontrolled versus controlled glycemia (adjusted odds ratio [aOR] 2.50 95%CI 1.61, 6.05, P = 0.042; aOR 4.78 95% CI 1.61,14.23, P<0.001) and more likely to have consistently-uncontrolled versus consistently-controlled glycemia (adjusted relative risk ratio [aRRR] 5.14 95% CI 1.37, 19.20, P = 0.015; aRRR 10.24 95% CI 0.07, 0.95, P = 0.003). Relapse cases of TB were less likely than new cases to have uncontrolled (aOR 0.20 95%CI 0.06, 0.63, P = 0.031) or consistently-uncontrolled (aRRR 0.25 95%CI 0.07, 0.95, P = 0.042) versus controlled glycemia. Those with long-term DM, suggested by previous diagnosis, glucose-lowering medication use and possibly central obesity, may require additional support to manage blood glucose during TB treatment.

Type 2 diabetes mellitus in patients with ischemic stroke - A nationwide study.

Type 2 diabetes (T2D) is a risk factor for ischemic stroke (IS) and associated with an adverse prognosis. Both stroke and diabetes care has evolved substantially during the last decade. This study aimed to determine the prevalence of T2D among IS patients along with time trends in the risk profile, use of glucose-lowering medications, quality-of-care and clinical outcomes, including stroke severity; length-of-stay; mortality, readmission and recurrent stroke in a large national cohort. Registry-based cohort study including all IS events in Denmark from 2004 to 2020. IS with co-morbid T2D were compared to IS without diabetes while adjusting for age, sex, stroke severity, co-morbidity and socio-economic factors. The study included 169,262 IS events; 24,479 with co-morbid T2D. The prevalence of T2D in IS increased from 12.0% (2004-2006) to 17.0% (2019-2020). The adjusted absolute 30-day mortality risk in IS with T2D decreased from 9.9% (2004-2006) to 7.8% (2019-2020). The corresponding adjusted risk ratios (aRR) were 1.22 95% confidence interval (1.09-1.37) and 1.29 (1.11-1.50), respectively. The aRR of 365-day mortality was in 2004-2006: 1.20 (1.12-1.29) and in 2019-2020: 1.34 (1.22-1.47). The 30- and 365-day readmissions rates were also consistently higher in IS with T2D. The prevalence of T2D in IS increased over time. The 30- and 365-day mortality rates decreased over the time-period but were consistently higher in IS with co-morbid T2D. Readmissions were also higher in IS with T2D. This highlights an urgent need for strategies to further improve the prognosis in IS patients with co-morbid T2D.

Integration of a fasting-mimicking diet programme in primary care for type 2 diabetes reduces the need for medication and improves glycaemic control: a 12-month randomised controlled trial.

The aim of this study was to evaluate the impact on metabolic control of periodic use of a 5-day fasting-mimicking diet (FMD) programme as an adjunct to usual care in people with type 2 diabetes under regular primary care surveillance. In this randomised, controlled, assessor-blinded trial, people with type 2 diabetes using metformin as the only glucose-lowering drug and/or diet for glycaemic control were randomised to receive 5-day cycles of an FMD monthly as an adjunct to regular care by their general practitioner or to receive regular care only. The primary outcomes were changes in glucose-lowering medication (as reflected by the medication effect score) and HbA1c levels after 12 months. Moreover, changes in use of glucose-lowering medication and/or HbA1c levels in individual participants were combined to yield a clinically relevant outcome measure ('glycaemic management'), which was categorised as improved, stable or deteriorated after 1 year of follow-up. Several secondary outcome measures were also examined, including changes in body weight. One hundred individuals with type 2 diabetes, age 18-75 years, BMI ≥27 kg/m2, were randomised to the FMD group (n=51) or the control group (n=49). Eight FMD participants and ten control participants were lost to follow-up. Intention-to-treat analyses, using linear mixed models, revealed adjusted estimated treatment effects for the medication effect score (-0.3; 95% CI -0.4, -0.2; p<0.001), HbA1c (-3.2 mmol/mol; 95% CI -6.2, -0.2 and -0.3%; 95% CI -0.6, -0.0; p=0.04) and body weight (-3.6 kg; 95% CI -5.2, -2.1; p<0.001) at 12 months. Glycaemic management improved in 53% of participants using FMD vs 8% of control participants, remained stable in 23% vs 33%, and deteriorated in 23% vs 59% (p<0.001). Integration of a monthly FMD programme in regular primary care for people with type 2 diabetes who use metformin as the only glucose-lowering drug and/or diet for glycaemic control reduces the need for glucose-lowering medication, improves HbA1c despite the reduction in medication use, and appears to be safe in routine clinical practice. ClinicalTrials.gov NCT03811587 FUNDING: The project was co-funded by Health~Holland, Top Sector Life Sciences & Health, the Dutch Diabetes Foundation and L-Nutra.

Effects of statin therapy on diagnoses of new-onset diabetes and worsening glycaemia in large-scale randomised blinded statin trials: an individual participant data meta-analysis

Previous meta-analyses of summary data from randomised controlled trials have shown that statin therapy increases the risk of diabetes, but less is known about the size or timing of this effect, or who is at greatest risk. We aimed to address these gaps in knowledge through analysis of individual participant data from large, long-term, randomised, double-blind trials of statin therapy. We conducted a meta-analysis of individual participant data from randomised controlled trials of statin therapy that participated in the CTT Collaboration. All double-blind randomised controlled trials of statin therapy of at least 2 years' scheduled duration and with at least 1000 participants were eligible for inclusion in this meta-analysis. All recorded diabetes-related adverse events, treatments, and measures of glycaemia were sought from eligible trials. Meta-analyses assessed the effects of allocation to statin therapy on new-onset diabetes (defined by diabetes-related adverse events, use of new glucose-lowering medications, glucose concentrations, or HbA1c values) and on worsening glycaemia in people with diabetes (defined by complications of glucose control, increased use of glucose-lowering medication, or HbA1c increase of ≥0·5%). Standard inverse-variance-weighted meta-analyses of the effects on these outcomes were conducted according to a prespecified protocol. Of the trials participating in the CTT Collaboration, 19 trials compared statin versus placebo (123 940 participants, 25 701 [21%] with diabetes; median follow-up of 4·3 years), and four trials compared more versus less intensive statin therapy (30 724 participants, 5340 [17%] with diabetes, median follow-up of 4·9 years). Compared with placebo, allocation to low-intensity or moderate-intensity statin therapy resulted in a 10% proportional increase in new-onset diabetes (2420 of 39 179 participants assigned to receive a statin [1·3% per year] vs 2214 of 39 266 participants assigned to receive placebo [1·2% per year]; rate ratio [RR] 1·10, 95% CI 1·04-1·16), and allocation to high-intensity statin therapy resulted in a 36% proportional increase (1221 of 9935 participants assigned to receive a statin [4·8% per year] vs 905 of 9859 participants assigned to receive placebo [3·5% per year]; 1·36, 1·25-1·48). For each trial, the rate of new-onset diabetes among participants allocated to receive placebo depended mostly on the proportion of participants who had at least one follow-up HbA1c measurement; this proportion was much higher in the high-intensity than the low-intensity or moderate-intensity trials. Consequently, the main determinant of the magnitude of the absolute excesses in the two types of trial was the extent of HbA1c measurement rather than the proportional increase in risk associated with statin therapy. In participants without baseline diabetes, mean glucose increased by 0·04 mmol/L with both low-intensity or moderate-intensity (95% CI 0·03-0·05) and high-intensity statins (0·02-0·06), and mean HbA1c increased by 0·06% (0·00-0·12) with low-intensity or moderate-intensity statins and 0·08% (0·07-0·09) with high-intensity statins. Among those with a baseline measure of glycaemia, approximately 62% of new-onset diabetes cases were among participants who were already in the top quarter of the baseline distribution. The relative effects of statin therapy on new-onset diabetes were similar among different types of participants and over time. Among participants with baseline diabetes, the RRs for worsening glycaemia were 1·10 (1·06-1·14) for low-intensity or moderate-intensity statin therapy and 1·24 (1·06-1·44) for high-intensity statin therapy compared with placebo. Statins cause a moderate dose-dependent increase in new diagnoses of diabetes that is consistent with a small upwards shift in glycaemia, with the majority of new diagnoses of diabetes occurring in people with baseline glycaemic markers that are close to the diagnostic threshold for diabetes. Importantly, however, any theoretical adverse effects of statins on cardiovascular risk that might arise from these small increases in glycaemia (or, indeed, from any other mechanism) are already accounted for in the overall reduction in cardiovascular risk that is seen with statin therapy in these trials. These findings should further inform clinical guidelines regarding clinical management of people taking statin therapy. British Heart Foundation, UK Medical Research Council, and Australian National Health and Medical Research Council.

Diabetes mellitus and response to IL-1 blockade with Anakinra after ST-elevation myocardial infarction: a pooled analysis of the VCU-ART studies

Abstract Background ST segment elevation myocardial infarction (STEMI) elicits an intense inflammatory response which is thought to contribute to subsequent maladaptive myocardial healing and remodeling, ultimately leading to heart failure (HF). The interleukin-1 (IL-1) blocker anakinra administered during the first 14 days after STEMI patients has been shown to effectively dampen the inflammatory response and reduce the incidence of HF events in pilot randomized controlled trials. Diabetes mellitus is a condition of enhanced systemic inflammation. Purpose To assess the role of diabetes mellitus as a modulating factor in respect to the efficacy of anakinra treatment during the first 14 days after STEMI. Methods We conducted a pooled analysis of three previous proof of principle trials on anakinra in STEMI. Diabetes mellitus was defined based on clinical history, use of glucose-lowering medications, or elevated hemoglobin A1c &amp;gt;6.5% at time of enrollment and further characterized as type I or type II based on the available clinical assessment. The area-under-the-curve for C reactive protein (AUC-CRP) at 14 days was used as a measure of the systemic inflammatory response during STEMI. The clinical endpoint was composite of death, hospitalizations for HF and urgent HF visits. Results The study population included 139 patients, of whom 39 (28%) had a diagnosis of diabetes mellitus at time of enrolment, all with type II. Median age was 56 [49-63] and 56 [49-63] years in patients with and without diabetes, respectively (p=0.652). There were 29 (21%) female and 52 (37%) Black-African American patients among those with diabetes compared to 29 (21%) female and 52 (37%) Black-African American patients in those without diabetes (p=0.69 and p=0.16, respectively). Treatment with anakinra (N=84) significantly dampened acute inflammation associated with STEMI in patients with diabetes (AUC-CRP 223 [117-399] vs 76 [42-148] mg•day/L, p&amp;lt;0.001) and in those without diabetes (AUC-CRP 223 [117-399] vs 76 [42-148] mg•day/L, p&amp;lt;0.001 – Figure 1). No statistically significant interaction between diabetes status and treatment with anakinra on outcomes was detected (pint=0.92): treatment with anakinra was associated with a hazard ratio [HR] 0.28 [0.09-0.84](p=0.02) in non-diabetic patients and HR 0.26 [0.11-1.32](p=0.10) in diabetic patients – Figure 2. Conclusion In this pooled analysis of the VCU-ART trials, the presence of type II diabetes mellitus showed no interaction with the efficacy of the treatment with anakinra early after STEMI in reducing the systemic inflammatory response or preventing new onset heart failure, hospitalization for HF or death.Figure 1.Figure 2

The impact of type 2 diabetes and glycaemic control on mortality and clinical outcomes in hospitalized patients with COVID-19 in the capital region of Denmark.

To explore the impact of type 2 diabetes (T2D), glycaemic control and use of glucose-lowering medication on clinical outcomes in hospitalized patients with COVID-19. For all patients admitted to a hospital in the Capital Region of Denmark (1 March 2020 to 1 December 2021) with confirmed COVID-19, we extracted data on mortality, admission to intensive care unit (ICU), demographics, comorbidities, medication use and laboratory tests from the electronic health record system. We compared patients with T2D to patients without diabetes using Cox proportional hazards models adjusted for available confounding variables. Outcomes were 30-day mortality and admission to an ICU. For patients with T2D, we also analysed the association of baseline haemoglobin A1c (HbA1c) levels and use of specific glucose-lowering medications with the outcomes. In total, 4430 patients were analysed, 1236 with T2D and 2194 without diabetes. The overall 30-day mortality was 19% (n = 850) and 10% (n = 421) were admitted to an ICU. Crude analyses showed that patients with T2D both had increased mortality [hazard ratio (HR) 1.37; 95% CI 1.19-1.58] and increased risk of ICU admission (HR 1.28; 95% CI 1.04-1.57). When adjusted for available confounders, this discrepancy was attenuated for both mortality (adjusted HR 1.13; 95% CI 0.95-1.33) and risk of ICU admission (adjusted HR 1.01; 95% CI 0.79-1.29). Neither baseline haemoglobin A1c nor specific glucose-lowering medication use were significantly associated with the outcomes. Among those hospitalized for COVID-19, patients with T2D did not have a higher risk of death and ICU admission, when adjusting for confounders.

Effect of Postmenopausal Hormone Therapy on Glucose Regulation in Women With Type 1 or Type 2 Diabetes: A Systematic Review and Meta-analysis.

Blood glucose regulation in women with diabetes may change during and after menopause, which could be attributed, in part, to decreased estrogen levels. To determine the effect of postmenopausal hormone therapy (HT) on HbA1c, fasting glucose, postprandial glucose, and use of glucose-lowering drugs in women with type 1 and women with type 2 diabetes. We conducted a systematic search of MEDLINE, Embase, Scopus, the Cochrane Library, and the ClinicalTrials.gov registry to identify randomized controlled trials (RCTs). We selected RCTs on the effect of HT containing estrogen therapy in postmenopausal women (≥12 months since final menstrual period) with type 1 or type 2 diabetes. Data were extracted for the following outcomes: HbA1c, fasting glucose, postprandial glucose, and use of glucose-lowering medication. Nineteen RCTs were included (12 parallel-group trials and 7 crossover trials), with a total of 1,412 participants, of whom 4.0% had type 1 diabetes. HT reduced HbA1c (mean difference -0.56% [95% CI -0.80, -0.31], -6.08 mmol/mol [95% CI -8.80, -3.36]) and fasting glucose (mean difference -1.15 mmol/L [95% CI -1.78, -0.51]). Of included studies, 50% were at high risk of bias. When postmenopausal HT is considered for menopausal symptoms in women with type 2 diabetes, HT is expected to have a neutral-to-beneficial impact on glucose regulation. Evidence for the effect of postmenopausal HT in women with type 1 diabetes was limited.

Development and validation of a prediction model based on machine learning algorithms for predicting the risk of heart failure in middle-aged and older US people with prediabetes or diabetes.

The purpose of this study was to develop and validate a machine learning (ML) based prediction model for the risk of heart failure (HF) in patients with prediabetes or diabetes. We used 3527 subjects aged 40 years and older with a prior diagnosis of prediabetes or diabetes from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018. The search for independent risk variables linked to HF was conducted using univariate and multivariable logistic regression analysis. The 3527 subjects were randomly divided into training set and validation set in a 7:3 ratio. Five ML models were built on the training set using five ML algorithms, including random forest (RF), and then validated on the validation set. Receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis and Bootstrap resampling method were used to measure the predictive performance of the five ML models. Multivariate logistic regression analysis showed that age, poverty-to-income ratio, myocardial infarction condition, coronary heart disease condition, chest pain condition, and glucose-lowering medication use were independent predictors of HF. By comparing the performance of the five ML models, the RF model (AUC = 0.978) was the best prediction model. The risk of HF in middle-aged and elderly patients with prediabetes or diabetes can be accurately predicted using ML models. The best prediction performance is presented by RF model, which can assist doctors in making clinical decisions.

Subgroups of adult-onset diabetes: a data-driven cluster analysis in a Ghanaian population

Adult-onset diabetes mellitus (here: aDM) is not a uniform disease entity. In European populations, five diabetes subgroups have been identified by cluster analysis using simple clinical variables; these may elucidate diabetes aetiology and disease prognosis. We aimed at reproducing these subgroups among Ghanaians with aDM, and establishing their importance for diabetic complications in different health system contexts. We used data of 541 Ghanaians with aDM (age: 25–70 years; male sex: 44%) from the multi-center, cross-sectional Research on Obesity and Diabetes among African Migrants (RODAM) Study. Adult-onset DM was defined as fasting plasma glucose (FPG) ≥ 7.0 mmol/L, documented use of glucose-lowering medication or self-reported diabetes, and age of onset ≥ 18 years. We derived subgroups by cluster analysis using (i) a previously published set of variables: age at diabetes onset, HbA1c, body mass index, HOMA-beta, HOMA-IR, positivity of glutamic acid decarboxylase autoantibodies (GAD65Ab), and (ii) Ghana-specific variables: age at onset, waist circumference, FPG, and fasting insulin. For each subgroup, we calculated the clinical, treatment-related and morphometric characteristics, and the proportions of objectively measured and self-reported diabetic complications. We reproduced the five subgroups: cluster 1 (obesity-related, 73%) and cluster 5 (insulin-resistant, 5%) with no dominant diabetic complication patterns; cluster 2 (age-related, 10%) characterized by the highest proportions of coronary artery disease (CAD, 18%) and stroke (13%); cluster 3 (autoimmune-related, 5%) showing the highest proportions of kidney dysfunction (40%) and peripheral artery disease (PAD, 14%); and cluster 4 (insulin-deficient, 7%) characterized by the highest proportion of retinopathy (14%). The second approach yielded four subgroups: obesity- and age-related (68%) characterized by the highest proportion of CAD (9%); body fat-related and insulin-resistant (18%) showing the highest proportions of PAD (6%) and stroke (5%); malnutrition-related (8%) exhibiting the lowest mean waist circumference and the highest proportion of retinopathy (20%); and ketosis-prone (6%) with the highest proportion of kidney dysfunction (30%) and urinary ketones (6%). With the same set of clinical variables, the previously published aDM subgroups can largely be reproduced by cluster analysis in this Ghanaian population. This method may generate in-depth understanding of the aetiology and prognosis of aDM, particularly when choosing variables that are clinically relevant for the target population.

621-P: Subphenotyping of Type 2 Diabetes Based on Pathophysiology and Its Association with Diabetes Remission in Urban Indians

Background and Aim: Sub-classification of type 2 diabetes (T2D) based on pathophysiological abnormalities is documented to facilitate better T2D management. Aim of the study was to classify 270 Indian patients with recently diagnosed T2D based on phenotype and the impact of each phenotype on the rate of remission, after a structured diabetes remission program. Methods: We retrospectively extracted and analyzed baseline data of patients with T2D (diagnosed as per WHO criteria) enrolled for a one-year diabetes management program at the Freedom from Diabetes Clinic, India. Inclusion criteria included a recent diagnosis of T2D (&amp;lt;2 years). Using the homeostatic assessment model, patients were categorized into 3 sub-phenotypes: insulinopenic (high insulin sensitivity (IS) and low beta cell function (BCF)), classical (low IS and low BCF), and hyperinsulinemic (low IS and high BCF) T2D. Post-intervention, remission was defined as maintaining HbA1c&amp;lt;48 mmol/mol without the use of glucose-lowering medications for at least 3 months. Results: Of the 270 patients, the majority were hyperinsulinemic (35.9%) followed by insulinopenic 17.4% and classical (13.3%) T2D. Additionally, a novel category of patients with both high IS and high BCF was observed (labeled ‘Unclassified’-33%). Hyperinsulinemic patients had the highest BMI (median 28 kg/m2), dyslipidemia, hypertension, and history of heart disease with the lowest remission rate (14.4%). One in four classical patients was on oral hypoglycemic agents and showed poor glycemic control but 25% remission. Unclassified patients showed the highest remission (28.1%). Conclusion: Pathophysiological sub-phenotyping could assist caregivers in better management of T2D through targeted treatment options. Remission rates were observed to be better in classical and unclassified (high insulin sensitivity and beta function) T2D. Further large-scale studies to understand the unclassified group are warranted. Disclosure P.Tripathi: Board Member; Freedom from Diabetes Clinic. A.R.Vyawahare: Research Support; Freedom From Diabetes. N.S.Kadam: Research Support; Freedom from Diabetes Clinic. B.Sharma: Research Support; Freedom From Diabetes clinic. M.H.Ganla: Employee; Freedom from Diabetes Clinic. M.Das biswas: Employee; Freedom from Diabetes Clinic. B.D.Saboo: None.

Atherosclerotic Cardiovascular Disease in Type2 Diabetes: A Retrospective, Observational Study of Economic and Clinical Burden in Sweden.

Individuals with type2 diabetes (T2D) are at high risk of experiencing atherosclerotic cardiovascular disease (ASCVD), which is associated with morbidity, mortality and healthcare resource utilisation. Clinical guidelines recommend the use of glucose-lowering medications with cardiovascular benefits in individuals with T2D and cardiovascular disease, but there is evidence that this is not reflected in clinical practice. We used linked national registry data from Sweden to compare outcomes in people with T2D and ASCVD against matched controls with T2D without ASCVD, over 5years. Direct costs (inpatient, outpatient and selected drug costs), indirect costs resulting from work absence, early retirement, cardiovascular events and mortality were examined. Individuals with T2D who were at least 16years old and were alive and resident in Sweden on 1January 2012 were identified in an existing database. In four separate analyses, individuals with a record indicating ASCVD according to a broad definition, peripheral artery disease (PAD), stroke or myocardial infarction (MI) before 1January 2012 were identified using diagnosis and/or procedure codes and propensity score matched 1:1 to controls with T2D and without ASCVD, using covariates for birth, sex and level of education in 2012. Follow-up continued until death, migration from Sweden or the end of the study period in 2016. In total, 80,305 individuals with ASCVD, 15,397 individuals with PAD, 17,539 individuals with previous stroke and 25,729 individuals with previous MI were included. Total mean annual costs per person were €14,785 for PAD (2.7 × costs for controls), €11,397 for previous stroke (2.2 × controls), €10,730 for ASCVD (1.9 × controls) and €10,342 for previous MI (1.7 × controls). Indirect costs and costs of inpatient care were the major cost drivers. ASCVD, PAD, stroke and MI were all associated with an increased likelihood of early retirement, cardiovascular events and mortality. ASCVD is associated with considerable costs, morbidity and mortality in individuals with T2D. These results support structured assessment of ASCVD risk and broader implementation of guideline-recommended treatments in T2D healthcare.

Seven-Year Results of a Randomized Trial Comparing Banded Roux-en-Y Gastric Bypass to Sleeve Gastrectomy for Type 2 Diabetes and Weight Loss.

Laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG) are common bariatric procedures that are effective in treating type 2 diabetes (T2D) in patients with obesity. Limited data from randomized trials are available comparing longevity of diabetes remission directly between the two procedures beyond 5years. A prospective, randomized, parallel, two-arm, clinical trial comparing the outcomes of silastic ring (SR)-LRYGB versus LSG was conducted at a single (Auckland, New Zealand) center. Patients and researchers were blinded until the 5-year mark and follow-up after this was unblinded. Eligible patients had T2D of > 6months duration with a BMI 35--65kg/m2 and were aged 20-55years. Randomization was 1:1 to SR-LRYGB and LSG following induction of anesthesia and was stratified by age group, BMI group, ethnicity, diabetes duration, and insulin therapy. The primary outcome was T2D remission, defined as HbA1c < 6% (42mmol/mol), without the use of glucose-lowering medications. A total of 114 patients were randomized of whom 6 died before the 7-year follow-up (2 SR-LRYGB, 4 LSG). Diabetes remission, assessed in 89 (82.4%) of the remaining patients, was seen in 23/50 (46.0%) after SR-LRYGB and 12/39 (30.8%) after LSG (adjusted OR 4.64, 95% CI 1.39, 15.52, p = 0.013). Percentage total body weight loss was greater after SR-LRYGB than LSG (26.2% vs 13.4%; absolute difference 12.8%; 95% CI 7.2%, 18.2%; p < 0.001). Complication rates were similar between groups. SR-LRYGB was superior to LSG for diabetes remission and weight loss at 7years following surgery, with acceptable complication rates.

Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis

Aims/hypothesisEpidemiological studies have generated conflicting findings on the relationship between glucose-lowering medication use and cancer risk. Naturally occurring variation in genes encoding glucose-lowering drug targets can be used to investigate the effect of their pharmacological perturbation on cancer risk.MethodsWe developed genetic instruments for three glucose-lowering drug targets (peroxisome proliferator activated receptor γ [PPARG]; sulfonylurea receptor 1 [ATP binding cassette subfamily C member 8 (ABCC8)]; glucagon-like peptide 1 receptor [GLP1R]) using summary genetic association data from a genome-wide association study of type 2 diabetes in 148,726 cases and 965,732 controls in the Million Veteran Program. Genetic instruments were constructed using cis-acting genome-wide significant (p<5×10−8) SNPs permitted to be in weak linkage disequilibrium (r2<0.20). Summary genetic association estimates for these SNPs were obtained from genome-wide association study (GWAS) consortia for the following cancers: breast (122,977 cases, 105,974 controls); colorectal (58,221 cases, 67,694 controls); prostate (79,148 cases, 61,106 controls); and overall (i.e. site-combined) cancer (27,483 cases, 372,016 controls). Inverse-variance weighted random-effects models adjusting for linkage disequilibrium were employed to estimate causal associations between genetically proxied drug target perturbation and cancer risk. Co-localisation analysis was employed to examine robustness of findings to violations of Mendelian randomisation (MR) assumptions. A Bonferroni correction was employed as a heuristic to define associations from MR analyses as ‘strong’ and ‘weak’ evidence.ResultsIn MR analysis, genetically proxied PPARG perturbation was weakly associated with higher risk of prostate cancer (for PPARG perturbation equivalent to a 1 unit decrease in inverse rank normal transformed HbA1c: OR 1.75 [95% CI 1.07, 2.85], p=0.02). In histological subtype-stratified analyses, genetically proxied PPARG perturbation was weakly associated with lower risk of oestrogen receptor-positive breast cancer (OR 0.57 [95% CI 0.38, 0.85], p=6.45×10−3). In co-localisation analysis, however, there was little evidence of shared causal variants for type 2 diabetes liability and cancer endpoints in the PPARG locus, although these analyses were likely underpowered. There was little evidence to support associations between genetically proxied PPARG perturbation and colorectal or overall cancer risk or between genetically proxied ABCC8 or GLP1R perturbation with risk across cancer endpoints.Conclusions/interpretationOur drug target MR analyses did not find consistent evidence to support an association of genetically proxied PPARG, ABCC8 or GLP1R perturbation with breast, colorectal, prostate or overall cancer risk. Further evaluation of these drug targets using alternative molecular epidemiological approaches may help to further corroborate the findings presented in this analysis.Data availabilitySummary genetic association data for select cancer endpoints were obtained from the public domain: breast cancer (https://bcac.ccge.medschl.cam.ac.uk/bcacdata/); and overall prostate cancer (http://practical.icr.ac.uk/blog/). Summary genetic association data for colorectal cancer can be accessed by contacting GECCO (kafdem at fredhutch.org). Summary genetic association data on advanced prostate cancer can be accessed by contacting PRACTICAL (practical at icr.ac.uk). Summary genetic association data on type 2 diabetes from Vujkovic et al (Nat Genet, 2020) can be accessed through dbGAP under accession number phs001672.v3.p1 (pha004945.1 refers to the European-specific summary statistics). UK Biobank data can be accessed by registering with UK Biobank and completing the registration form in the Access Management System (AMS) (https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access).Graphical

Associations of baseline glycemic status and its transitions with cognitive and physical functioning decline

ObjectiveEvidence about the decline of cognition and physical function across glycemic status (normoglycemia, prediabetes, and diabetes) is inconsistent. We evaluated longitudinal changes in cognition and physical function according to glycemic status and also different glycemic transitions. Study designPopulation-based cohort study. Methods9307 participants (mean age 59.7 years, 53.7 % women) were included from the China Health and Retirement Longitudinal Study (2011–2018). Global cognition (assessed by orientation, memory, and executive function) and physical function (calculated as the sum of impaired basic and instrumental activities of daily living) were assessed in each wave. The glycemic status was assessed in waves 2011 and 2015. Diabetes was defined as fasting blood glucose ≥7.0 mmol/L, HbA1c ≥6.5 %, self-reported diabetes, or glucose-lowering medication use. Prediabetes was defined as fasting blood glucose 5.6–6.9 mmol/L or an HbA1c of 5.7–6.4 %. ResultsCompared with normoglycemia, baseline diabetes was associated with a faster decline in orientation (−0.018 SD/year, 95%CI -0.032, −0.004) and a faster increase in physical function score (0.082 /year, 95%CI 0.038, 0.126). We did not observe any effect of prediabetes on the changing rate of cognition and physical function. Progression from normoglycemia to diabetes between waves 2011 and 2015 was associated with a significantly faster decline in global cognition, memory, executive function, and physical function compared with stable normoglycemia. ConclusionsBaseline diabetes was associated with accelerated decline of cognition and physical function. Associations with prediabetes were not observed, suggesting an important short diagnostic window when diabetes presents de novo.

Achieving Effective Weight Loss for Type 2 Diabetes Mellitus Control: From Evidence to Practice

Type 2 diabetes mellitus (T2DM) poses a significant public health concern in Singapore. It is well established that T2DM is strongly associated with obesity. In Singapore, the prevalence of obesity and overweight in adults has been increasing over the last two decades. By 2050, the prevalence of obesity in the nation is predicted to reach 15.9 percent, a rise from 4.3 percent in 1990. The total prevalence of T2DM is also projected to rise to 15 percent in 2050, which was 7.3 percent in 1990, in tandem with the rise in obesity prevalence. Moderate and sustained weight loss (5-10 percent) improves glycaemic control and cardiovascular risk factors in overweight or obese patients with T2DM. Disease-modifying effects in T2DM and improvement in long-term cardiovascular outcomes and mortality are associated with larger and sustained weight losses (&gt;10 percent). In this article, we highlight the growing burden of T2DM and its complications in Singapore and the role of weight loss in T2DM control. This article aims to provide an overview of multidisciplinary/multipronged strategies (lifestyle interventions, patient-centred approach with preferential use of glucose-lowering medications of weight neutral/weight loss effect, consideration of pharmacotherapy for weight loss and metabolic surgery) to achieve effective weight loss for T2DM control.

Continuity of Medication Use by US Adults With Diabetes, 2005-2019

Consistent medication use is critical for diabetes management. Population surveillance of consistency of medication use may identify opportunities to improve diabetes care. To evaluate trends in longitudinal use of glucose-, blood pressure-, and lipid-lowering medications by adults with diabetes. This serial cross-sectional study assessed trends in longitudinal use of glucose-, blood pressure-, and lipid-lowering medications by adults with diagnosed diabetes participating in the Medical Expenditure Panel Survey (MEPS), which allows serial cross-sections and 2-year longitudinal follow-up, between the 2005 to 2006 panel and 2018 to 2019 panel. Population-weighted, nationally representative estimates for the US were reported. Included individuals were adult MEPS participants with diagnosed diabetes during both years (ie, during 2005 and 2006 or during 2018 and 2019) who participated in all survey rounds. Data were analyzed from August 2021 to November 2022. Longitudinal use over the 2 years was categorized as continued use (at least 1 fill per year), no use, inconsistent use, and new use by medication type (glucose-, blood pressure-, and lipid-lowering medications). New medications were defined as prescription fills for a medication type first prescribed and filled in year 2 of MEPS participation. A total of 15 237 participants with diabetes (7222 individuals aged 45-64 years [47.4%]; 8258 [54.2%] female participants; 3851 Latino [25.3%]; 3619 non-Latino Black (23.8%), and 6487 non-Latino White [42.6%]) were included in the analytical sample. A mean of 19.5% (95% CI, 18.6%-20.3%), 17.1% (95% CI, 16.2%-18.1%), and 43.3% (95% CI, 42.2%-44.3%) of participants did not maintain continuity in use of glucose-, blood pressure-, or lipid-lowering medications, respectively, during both years of follow-up. The proportion of participants who continued use of glucose-lowering medication in both years trended down from 84.5% (95% CI, 81.8%-87.3%) in 2005 to 2006 to 77.4% (95% CI, 74.8%-80.1%) in 2018 to 2019; this decrease coincided with rate increases in inconsistent use (3.3% [95% CI, 1.9%-4.7%] in 2005-2006 to 7.1% [95% CI, 5.6%-8.6%] in 2018-2019) and no use (8.1% [95% CI, 6.0%-10.1%] in 2005-2006 to 12.9% [95% CI, 10.9%-14.9%] in 2018-2019). Inconsistent use of blood pressure-lowering medications trended upward from 3.9% (95% CI, 1.8%-6.0%) in 2005 to 2006 to 9.0% (95% CI, 7.0%-11.0%) in 2016 to 2017. Inconsistent use of lipid-lowering medication trended up to a high of 9.9% (95% CI, 7.0%-12.7%) in 2017 to 2018. This study found that a mean of 19.5% of participants did not maintain continuity in use of glucose-lowering medication, with recent decreases, while a mean of 17.1% and 43.2% of participants did not maintain continuity of use of blood pressure- or lipid-lowering medications, respectively.

Sex- and age-specific impacts of smoking, overweight/obesity, hypertension, and diabetes mellitus in the development of disabling dementia in a Japanese population.

Sex- and age-specific impacts of cardiovascular risk factors on the development of dementia have not been well evaluated. We investigated these impacts of smoking, overweight/obesity, hypertension, and diabetes mellitus on the risk of disabling dementia. The study participants were 25,029 (10,134 men and 14,895 women) Japanese aged 40-74 years without disabling dementia at baseline (2008-2013). They were assessed on smoking status (non-current or current), overweight/obesity (body mass index ≥25 kg/m2 and ≥30 kg/m2, respectively), hypertension (systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg or any antihypertensive medication use), and diabetes mellitus (a fasting serum glucose ≥126 mg/dL, non-fasting glucose ≥200 mg/dL, hemoglobin A1c ≥6.5% by the National Glycohemoglobin Standardization Program or glucose-lowering medication use) at baseline. Disabling dementia was identified as the level of care required ≥1 and cognitive disability grade ≥IIa according to the National Long-term Care Insurance Database. We used a Cox proportional regression model to estimate hazard ratios and 95% confidence intervals (95% CIs) of disabling dementia according to the cardiovascular risk factors and calculated the population attributable fractions (PAFs). During a median follow-up of 9.1 years, 1,322 (606 men and 716 women) developed disabling dementia. Current smoking and hypertension were associated with a higher risk of disabling dementia in both sexes, whereas overweight or obesity was not associated with the risk in either sex. Diabetes mellitus was associated with a higher risk only in women (p for sex interaction = 0.04). The significant PAFs were 13% for smoking and 14% for hypertension in men and 3% for smoking, 12% for hypertension, and 5% for diabetes mellitus in women. The total PAFs of the significant risk factors were 28% in men and 20% in women. When stratified by age, hypertension in midlife (40-64 years) was associated with the increased risk in men, while diabetes mellitus in later-life (65-74 years) was so in women. A substantial burden of disabling dementia was attributable to smoking, and hypertension in both sexes and diabetes mellitus in women, which may require the management of these cardiovascular risk factors to prevent dementia.