The association of isocarbophos and isofenphos with different types of glucose metabolism: The role of inflammatory cells.

To investigate the associations between isocarbophos and isofenphos with impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM), and to assess the mediation roles of inflammation cells. There were 2701 participants in the case-control study, including 896 patients with T2DM, 900 patients with IFG, 905 subjects with NGT. Plasma isocarbophos and isofenphos concentrations were measured using gas chromatography and triple quadrupole tandem mass spectrometry. Generalized linear models were used to calculate the relationships between plasma isofenphos and isocarbophos levels with inflammatory factor levels and T2DM. Inflammatory cell was used as mediators to estimate the mediating effects on the above associations. Isocarbophos and isofenphos were positively related with T2DM after adjusting for other factors. The odds ratio (95% confidence interval) (OR (95%CI)) for T2DM was 1.041 (1.015, 1.068) and for IFG was 1.066 (1.009, 1.127) per unit rise in ln-isocarbophos. The prevalence of T2DM increased by 6.4% for every 1 unit more of ln-isofenphos (OR (95% CI): 1.064 (1.041, 1.087)). Additionally, a 100% rise in ln-isocarbophos was linked to 3.3% higher ln-HOMA2IR and a 0.029 mmol/L higher glycosylated hemoglobin (HbA1c) (95% CI: 0.007, 0.051). While a 100% rise in ln-isofenphos was linked to increase in ln-HOMA2 and ln-HOMA2IR of 5.8% and 3.4%, respectively. Furthermore, white blood cell (WBC) and neutrophilic (NE) were found to be mediators in the relationship between isocarbophos and T2DM, and the corresponding proportions were 17.12% and 17.67%, respectively. Isofenphos and isocarbophos are associated with IFG and T2DM in the rural Chinese population, WBC and NE have a significant role in this relationship.

Puerarin ameliorates high glucose-induced MIN6 cell injury by activating PINK1/Parkin-mediated mitochondrial autophagy.

The dysfunction of pancreatic ß-cells plays a pivotal role in the pathogenesis of type 2 diabetes mellitus (T2DM). Despite numerous studies demonstrating the anti-inflammatory and antioxidant properties of puerarin, the protective effects of puerarin on ß-cells remain poorly understood. Hence, this study aimed to explore the effects of puerarin on ß-cell dysfunction in a hyperglycemic environment via the PINK/Parkin-mediated mitochondrial autophagy pathway. The alterations in cell viability of MIN6 cells exposed to glucose concentrations of 5 mM, 10 mM, 20 mM, and 30 mM for 24 h, 48 h, and 72 h, respectively, were assessed using the CCK-8 assay to optimize the modeling conditions. Subsequently, cellular insulin secretion was measured using enzyme-linked immunosorbent assay (ELISA), apoptosis rate by flow cytometry, mitochondrial membrane potential alteration by JC-1, cellular ROS production by the DCFH-DA fluorescent probe, and fusion of cellular autophagosomes and lysosomes through adenoviral infection analysis. Furthermore, gene and protein expression levels of the PINK/Parkin-mediated mitochondrial autophagy pathway and mitochondrial apoptosis pathway were assessed using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot, respectively. Results indicated a significant decrease in MIN6 cell viability following 48 h of exposure to 30 mM glucose concentration. Puerarin intervention markedly attenuated ROS production, restored mitochondrial membrane potential, induced PINK/Parkin-mediated mitochondrial autophagy, suppressed activation of the mitochondrial apoptotic pathway, mitigated apoptosis, and enhanced insulin secretion in a high glucose (HG) environment. The findings of this investigation contribute to a deeper understanding of the precise mechanism underlying the protective effects of puerarin on ß-cells and offer a theoretical foundation for advancing puerarin-based therapeutics aimed at ameliorating T2DM.

A systematic review and meta-analysis of ischemia-modified albumin in diabetes mellitus.

Aim: There is an ongoing search for novel biomarkers of diabetes. We conducted a systematic review and meta-analysis of the serum concentrations of ischemia-modified albumin (IMA), a candidate biomarker of oxidative stress, acidosis, and ischemia, in patients with pre-diabetes, different types of diabetes mellitus (type 1, T1DM, type 2, T2DM, and gestational, GDM), and healthy controls. Methods: We searched for case-control studies published in PubMed, Web of Science, and Scopus from inception to December 31, 2023. The risk of bias and the certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and GRADE, respectively. Results: In 29 studies, T2DM patients had significantly higher IMA concentrations when compared to controls (standard mean difference, SMD = 1.83, 95 % CI 1.46 to 2.21, p˂0.001; I2 = 95.7 %, p < 0.001; low certainty of evidence). Significant associations were observed between the SMD and glycated hemoglobin (p = 0.007), creatinine (p = 0.003), triglycerides (p = 0.029), and the presence of diabetes complications (p = 0.003). Similar trends, albeit in a smaller number of studies, were observed in T1DM (two studies; SMD = 1.59, 95 % CI -0.09 to 3.26, p˂0.063; I2 = 95.8 %, p < 0.001), GDM (three studies; SMD = 3.41, 95 % CI 1.14 to 5.67, p = 0.003; I2 = 97.0 %, p < 0.001) and pre-diabetes (three studies; SMD = 15.25, 95 % CI 9.86 to 20.65, p˂0.001; I2 = 99.3 %, p < 0.001). Conclusion: Our study suggests that IMA is a promising biomarker for determining the presence of oxidative stress, acidosis, and ischemia in pre-diabetes and T1DM, T2DM, and GDM. However, the utility of measuring circulating IMA warrants confirmation in prospective studies investigating clinical endpoints in pre-diabetes and in different types of diabetes (PROSPERO registration number: CRD42024504690).

Assessment of Health-Related Quality of Life and Its Determinants in Type 2 Diabetes Mellitus Patients: A Cross-Sectional Study.

Background Type 2 diabetes mellitus is a complex metabolic disorder associated with several complications that determine the quality of life of the patients. Health-related quality of life (HRQoL) is a measurable outcome of the self-perception of a patient's health which is affected due to age, lifestyle changes, medication, and treatment modalities. This study was undertaken to understand the impact of individual parameters of age, medication type and duration, diabetes-associated complications, and levels of glycated hemoglobin (HbA1c) on the quality of life (QoL) of the patient.  Methodology This single-center prospective, cross-sectional study was conducted at the Indira Gandhi Institute of Medical Sciences (IGIMS), Patna, Bihar, India. Participants were recruited from the Outpatient Department of General Medicine, IGIMS. HRQoL was measured using a validated and reliable EuroQol 5-dimensions 5-levels (EQ-5D-5L) questionnaire developed by the EuroQol Research Foundation, along with the EuroQol-Visual Analogue Scale (EQ-VAS). The eligibility criteria included adult diabetic patients above 18 years of age with complete medical records, who had been treated at the outpatient department for a minimum of three months and could be interviewed. Results The results from this study show that 46% of the patients belonged to the age group of 45-65 years. The quality of health index scores and EQ-VAS scores significantly correlated with age (p-values: 1.11 e-4 and 3.09 e-5; <0.05). Of the subjects, 66.4%, 6.7%, and 26.8% were under oral hypoglycaemic agents (OHA), insulin, and both insulin with OHA medications respectively. HbA1C levels were statistically significantly correlated with mobility, self-care, usual activities, pain or discomfort, and anxiety or depression (p-value 0.032; <0.05), along with self-perception of the patient's health (p-value 0.00026; <0.05). Also, the perception of having slight problems in mobility, self-care, usual activities, pain or discomfort, and anxiety or depression was similar irrespective of gender (EQ-5D-5L score for males: 9.47 and females: 9.3). Despite suffering from diabetes-associated chronic complications, 60.5% of the subjects perceived their overall health to be good as indicated by the scores. Conclusion The self-perception of HRQoL concerning mobility, self-care, usual activities, pain or discomfort, and anxiety or depression was correlated with age, duration of anti-diabetic medication, and HbA1C level. Good mobility, self-care, and performing usual activities reduce anxiety or depression as opposed to age, pain, and discomfort. However, the subjects in this study cohort perceived overall good health in themselves in terms of EQ-VAS and 5D-5L scores, indicating effective diabetic care and management options available to them.

Behavioral Changes in a Pediatric Patient With Sotos Syndrome: A Case Emphasizing the Importance of Coordinated Care.

Sotos syndrome is a rare overgrowth condition characterized by tall stature, distinctive facial features, and learning disabilities. It is primarily caused by a microdeletion of the nuclear receptor-binding set domain protein 1 (NSD1) gene on chromosome 5q35. Patients often present with various clinical manifestations, including tall stature, precocious puberty, cardiac anomalies, and mild intellectual disability. Management of Sotos syndrome involves a multidisciplinary approach due to its complex nature and potential comorbidities. This case discusses the management of a 10-year-old female with a known gene mutation consistent with Sotos syndrome that presented to the clinic with behavioral changes, and highlights the importance of integrated care models when addressing complex clinical scenarios.

ED-71 Ameliorates Bone Loss in Type 2 Diabetes Mellitus by Enhancing Osteogenesis Through Upregulation of the Circadian Rhythm Coregulator BMAL1.

Purpose: Bone loss is a common complication of type 2 diabetes mellitus (T2DM). Circadian rhythms play a significant role in T2DM and bone remodeling. Eldecalcitol (ED-71), a novel active vitamin D analog, has shown promise in ameliorating T2DM. We aimed to investigate whether the circadian rhythm coregulator BMAL1 mediates the anti-osteoporotic effect of ED-71 in T2DM and its associated mechanisms. Methods: A T2DM mouse model was established using high-fat diet (HDF) and streptozotocin (STZ) injection, and blood glucose levels were monitored weekly. HE staining, Masson staining, and Micro-CT were performed to assess the changes in bone mass. IHC staining and IF staining were used to detect osteoblast status and BMAL1 expression and RT-qPCR was applied to detect the change of oxidative stress factors. In vitro, high glucose (HG) stimulation was used to simulate the cell environment in T2DM. RT-qPCR, Western blot, IF, ALP staining and AR staining were used to detect osteogenic differentiation and SIRT1/GSK3ß signaling pathway. DCFH-DA staining was used to detect reactive oxygen species (ROS) levels. Results: ED-71 increased bone mass and promoted osteogenesis in T2DM mice. Moreover, ED-71 inhibited oxidative stress and promoted BMAL1 expression in osteoblasts The addition of STL1267, an agonist of the BMAL1 transcriptional repressor protein REV-ERB, reversed the inhibitory effect of ED-71 on oxidative stress and the promotional effect on osteogenic differentiation. In addition, ED-71 facilitated SIRT1 expression and reduced GSK3ß activity. The inhibition of SIRT1 with EX527 partially attenuated ED-71's effects, whereas the GSK3ß inhibitor LiCl further enhanced ED-71's positive effects on BMAL1 expression. Conclusion: ED-71 ameliorates bone loss in T2DM by upregulating the circadian rhythm coregulator BMAL1 and promoting osteogenesis through inhibition of oxidative stress. The SIRT1/GSK3ß signaling pathway is involved in the regulation of BMAL1.

Association Between COVID-19 and Diabetes Management Indices in Japanese Type 2 Diabetes Mellitus Patients: A Single-Center, Retrospective Study.

Purpose: The aim of the study was to determine the association between coronavirus disease 2019 (COVID-19) infection and diabetes management indices in patients with type 2 diabetes mellitus. Patients and Methods: A single-center, retrospective, observational study of patients with type 2 diabetes mellitus at Kenwakai Hospital (Nagano, Japan) was conducted. Data of 95 patients (mean age, 72 ± 12 years; men, 67.4%) who visited between March 1, 2019 and February 28, 2022 were obtained from the hospital's electronic information system. COVID-19 was diagnosed by a chemiluminescent enzyme immunoassay (CLEIA). Results: There was no association between COVID-19 infection and age, sex, hemodialysis treatment status, or the Charlson Comorbidity Index. After adjustment for possible confounding factors, the incidence of COVID-19 infection was significantly correlated with HbA1c ≥7.0% (odds ratio [OR], 5.51; 95% confidence interval [CI], 1.30-23.26). Conclusion: The results suggest an association between high HbA1c levels and COVID-19 infection in patients with type 2 diabetes mellitus. Appropriate management of diabetes mellitus, focusing on HbA1c levels, may help prevent COVID-19 infection and severe disease after infection.

Finerenone and left ventricular hypertrophy in chronic kidney disease and type 2 diabetes.

AIMS: Left ventricular hypertrophy (LVH) has been associated with an increased risk of cardiovascular (CV) disease and linked to increased morbidity and mortality. In patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), hypertension is common, and patients with these co-morbidities additionally have a high prevalence of LVH. This analysis of the prespecified pooled FIDELITY analysis comprising the randomized, double-blind, placebo-controlled, multicentre FIDELIO-DKD and FIGARO-DKD phase III studies aimed to explore the CV and kidney effects of finerenone, a nonsteroidal mineralocorticoid receptor antagonist, in patients with CKD and T2D stratified by a diagnosis of LVH at baseline. METHODS AND RESULTS: A diagnosis of LVH in the FIDELITY patient population was determined at baseline using investigator-reported electrocardiogram (ECG) findings. The two efficacy outcomes, assessed by baseline LVH, were the composite CV outcome of time to CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure (HHF), and a composite kidney outcome of time to onset of kidney failure, a sustained decrease in estimated glomerular filtration rate (eGFR) ≥57% from baseline over ≥4 weeks, or kidney-related death. Safety outcomes by baseline LVH were reported as treatment-emergent adverse events. At baseline out of 13 026 patients in FIDELITY, 96.5% had hypertension and 9.6% had investigator-reported LVH. The relative risk reduction for the composite CV and kidney outcomes with finerenone versus placebo was lower in the LVH subgroup; however, the treatment effect of finerenone was not modified by baseline LVH for either outcome (Pinteraction = 0.1075 for composite CV outcome and Pinteraction = 0.1782 for composite kidney outcome). Analysis of the composite CV outcome components showed a greater reduction in the risk of HHF versus placebo for patients with baseline LVH compared with those without (Pinteraction = 0.0024). Overall safety events were comparable between the LVH subgroups and treatment arms. Treatment-emergent hyperkalaemia was observed more frequently with finerenone versus placebo, but discontinuation rates were low in both treatment arms and between LVH subgroups. CONCLUSIONS: In conclusion, the overall CV and kidney benefits of finerenone versus placebo were not modified by the presence of LVH at baseline, with overall safety findings being similar between LVH subgroups. A greater benefit was observed for HHF in patients with versus without LVH, suggesting that LVH may be a predictor of the treatment effect of finerenone on HHF.

Glycemic status and effect on mortality: Multifactorial prevention programme for cardiovascular disease in Finnish primary care.

AIMS: To compare 13-year mortality rates in normoglycemic, prediabetic and diabetic subjects attending a community-based screening and intervention programme. METHODS: Population survey identified 2569 cardiovascular disease (CVD) white risk subjects aged 45-70 years and without manifested CVD or diabetes. Oral glucose tolerance test was performed, and multifactorial intervention was provided. Effect of glycemic status on mortality was estimated in models adjusted for age, gender, education years, smoking, body mass index, mean arterial pressure, total cholesterol, and physical activity. RESULTS: Of the subjects, 2055 (77 %) were normoglycemic, 380 (14 %) had prediabetes and 224 (9 %) diabetes. Compared to the normoglycemic group, the fully adjusted hazard ratios (HR) for all-cause mortality were 1.34 (95 % CI: 0.98-1.83) in the prediabetes group and 2.31 (95 % CI: 1.62-3.31) in the diabetes group. Standardized mortality rates were 0.63 (95 % CI: 0.54-0.73), 0.91 (95 % CI: 0.69-1.18), and 1.55 (95 % CI: 1.19-2.02) in the normoglycemic, prediabetes, and diabetes groups, respectively. The most common cause of death was cancer (42 % of all deaths), followed by CVD (28 %). CONCLUSIONS/INTERPRETATION: Screen-detected diabetes carries a substantial risk of death even after primary care intervention. The pattern of excess mortality has shifted towards cancer deaths.

Levels of plasma 25-hydroxy vitamin D and risk of developing type 2 diabetes in a large Danish primary health care population.

AIMS: Plasma levels of Vitamin D (25(OH)D) have been suggested as a predictor for developing type 2 diabetes. The purpose of this study was therefore to investigate if a measurement of plasma 25(OH)D could predict the development of type 2 diabetes in a cohort of 222,311 individuals from primary healthcare in Denmark. METHODS: The CopD-study database containing data from the Copenhagen General Practitioners Laboratory on blood tests conducted from April 2004 to January 2012 was used for identification of the study population. Incident type 2 diabetes was then defined as having at least two redeemed prescriptions of antidiabetics or at least two hospital contacts due to type 2 diabetes or one redeemed prescription and one hospital contact regarding type 2 diabetes. RESULTS: A total of 222,311 individuals were included in the study, of whom 7652 (3.4%) developed type 2 diabetes during the follow-up period of minimum one year. Individuals who developed type 2 diabetes had a significantly lower median 25(OH)D level than persons in the non-diabetes group. The hazard ratio for development of type 2 diabetes increased by 15% per 10 n mol/L decrease in 25(OH)D level. CONCLUSION: In this study of 222,311 persons from primary health care in Denmark, we found a clear inverse relationship between 25(OH)D and the risk of developing type 2 diabetes. Further studies should be conducted to clarify the mechanisms behind the relationship between 25(OH)D and type 2 diabetes and the effect of oral vitamin D supplementation on the development of type 2 diabetes.

Association Between Type 2 Diabetes Mellitus and Alzheimer's Disease: Common Molecular Mechanism and Therapeutic Targets.

Diabetes mellitus (DM) and Alzheimer's disease (AD) rates are rising, mirroring the global trend of an aging population. Numerous epidemiological studies have shown that those with Type 2 diabetes (T2DM) have an increased risk of developing dementia. These degenerative and progressive diseases share some risk factors. To a large extent, the amyloid cascade is responsible for AD development. Neurofibrillary tangles induce neurodegeneration and brain atrophy; this chain reaction begins with hyperphosphorylation of tau proteins caused by progressive amyloid beta (Aß) accumulation. In addition to these processes, it seems that alterations in brain glucose metabolism and insulin signalling lead to cell death and reduced synaptic plasticity in AD, before the onset of symptoms, which may be years away. Due to the substantial evidence linking insulin resistance in the brain with AD, researchers have coined the name "Type 3 diabetes" to characterize the condition. We still know little about the processes involved, even though current animal models have helped illuminate the links between T2DM and AD. This brief overview discusses insulin and IGF-1 signalling disorders and the primary molecular pathways that may connect them. The presence of GSK-3ß in AD is intriguing. These proteins' association with T2DM and pancreatic ß-cell failure suggests they might be therapeutic targets for both disorders.

Fracture risk revisited: Bone mineral density T-score and fracture risk in type 2 diabetes.

AIM: To study the association between femoral neck (FN) bone mineral density (BMD) T-score and fracture risk in individuals with and without type 2 diabetes (T2D). MATERIALS AND METHODS: We performed a single-centre retrospective cohort study using the Danish National Health Service. BMD of the FN was measured by dual-energy X-ray absorptiometry. Cox proportional hazards regression models were used to study the association between FN BMD T-score and fractures in individuals with and without T2D separately, adjusted for age, comorbidities and comedication. The results from this analysis were used to estimate the 10-year absolute fracture risk. RESULTS: In total, there were 35,129 women (2362 with T2D) and 7069 men (758 with T2D). The FN BMD T-score was significantly associated with risk of any, hip and major osteoporotic fracture in men and women with [adjusted hazard risk ratios (aHR) women, hip: 1.57; 95% confidence interval (CI) 1.24-2.00, incidence rate (IR) 8.7; aHR men, hip: 1.55; 95% CI 1.01-2.36, IR 4.6] and without T2D (aHR women, hip: 1.75; 95% CI 1.64-1.87, IR 7.0; aHR men, hip: 1.97, 95% CI 1.73-2.25, IR 6.3), and its ability to predict fracture risk was similar. Fracture IRs were not significantly different for individuals with or without T2D, nor was the estimated cumulative 10-year fracture risk. CONCLUSIONS: The FN BMD T-score was significantly associated with hip, non-spine and major osteoporotic fracture risk in men and women with and without T2D. Fracture risk for a given T-score and age was equal in individuals with and without T2D, as was the ability of the FN BMD T-score to predict fracture risk.

Brain Microvascular Pericyte Pathology Linking Alzheimer's Disease to Diabetes.

The brain microvasculature, which delivers oxygen and nutrients and forms a critical barrier protecting the central nervous system via capillaries, is deleteriously affected by both Alzheimer's disease (AD) and type 2 diabetes (T2D). T2D patients have an increased risk of developing AD, suggesting potentially related microvascular pathological mechanisms. Pericytes are an ideal cell type to study for functional links between AD and T2D. These specialized capillary-enwrapping cells regulate capillary density, lumen diameter, and blood flow. Pericytes also maintain endothelial tight junctions to ensure blood-brain barrier integrity, modulation of immune cell extravasation, and clearance of toxins. Changes in these phenomena have been observed in both AD and T2D, implicating "pericyte pathology" as a common feature of AD and T2D. This review examines the mechanisms of AD and T2D from the perspective of the brain microvasculature, highlighting how pericyte pathology contributes to both diseases. Our review identifies voids in understanding how AD and T2D negatively impact the brain microvasculature and suggests future studies to examine the intersections of these diseases.

Efficacy of lifestyle weight loss interventions on regression to normoglycemia and progression to type 2 diabetes in individuals with prediabetes: a systematic review and pairwise and dose-response meta-analyses.

BACKGROUND: Current recommendations for weight loss in individuals with prediabetes come from individual trials and are derived from older data. OBJECTIVE: To elucidate the dose-dependent impacts of weight loss on participants with prediabetes to determine the optimal magnitude of weight loss required for the implementation of the most effective diabetes prevention program. METHODS: We searched PubMed, Scopus, CENTRAL, CINAHL, and grey literature sources to September 2023 for randomized trials ≥6 months that evaluated the efficacy of a lifestyle weight loss intervention on participants with prediabetes. We conducted random-effects pairwise meta-analyses to calculate relative and absolute effects. We performed one-stage weighted mixed-effects meta-analysis to elucidate the dose-response curves. RESULTS: 44 randomized trials with 14,742 participants with prediabetes (intervention duration range: 6 to 72 months [median=24 months], average weight loss range: 1% to 9%) were included. Lifestyle weight loss interventions increased regression to normoglycemia by 11 per 100 participants (95%CI: 8 more, 17 more; risk ratio: 1.51, 95%CI: 1.27, 1.80; n=20 trials, GRADE=moderate), and reduced progression to type 2 diabetes by 8 per 100 participants (95%CI: 11 fewer, 6 fewer; risk ratio: 0.59, 95%CI: 0.51, 0.67; n=37, GRADE=moderate). There were no significant or credible differences among subgroups categorized by the type and duration of intervention. Dose-response meta-analyses indicated that the risk of regression to normoglycemia increased and the risk of progression to type 2 diabetes declined in a linear pattern within the range of weight loss from 1% to 9%. CONCLUSIONS: Over a median duration of 24 months, with weight loss ranging from 1% to 9%, the relationship between weight loss and the progression to type 2 diabetes, as well as the regression to normoglycemia, follows a linear pattern. Any form of lifestyle weight loss interventions including diet, exercise, or a combination of both, can have beneficial impacts on participants with prediabetes. PROTOCOL REGISTRATION: PROSPERO (CRD42023465322).

Efficacy of a health education technology program in improving adherence to self-management behaviors and quality of life among adults with type 2 diabetes: A randomized controlled trial.

AIM: This study examined the efficacy of a health education technology program on self-management adherence behavior and quality of life among people with type 2 diabetes (T2D). METHODS: A randomized experimental study design was employed. A total of 110 subjects was recruited. The experimental group received a novel technology education program plus routine shared care. The control group received routine shared care alone. Quality of life and adherence to self-management behavior questionnaires were used to measure outcomes. A linear mixed-effects model was used to analyze changes in quality of life after controlling for pre-test effects. The odds ratio was calculated for differences in adherence behavior between the two groups. RESULTS: The between-group mean difference in quality of life scores and adherence to physical activity comparing pre-test at 3 months follow-up showed significant progress at 3 months post-test compared with the control group. However, the increase in mean quality of life scores and adherence behavior at 6 months did not demonstrate a sustained between-group difference. CONCLUSION: The results showed adherence to physical activity and improved quality of life in patients with T2D at 3 months post intervention. Therefore, the program can be used as an intensive model for diabetes shared care.

A Systematic Approach to Evaluating Instrumental Variable Assumptions: Applied Example of Glucose-lowering Medications and Risk for Hospitalized Heart Failure in Older Adults.

One obstacle to adopting instrumental variable (IV) methods in pharmacoepidemiology is their reliance on strong, unverifiable assumptions. We can falsify IV assumptions by leveraging the causal structure, which can strengthen or refute their plausibility and increase the validity of effect estimates. We illustrate a systematic approach to evaluate calendar time IV assumptions in estimating the known effect of thiazolidinediones on hospitalized heart failure. Using cohort entry time before and after 09/2010, when the U.S. Food and Drug Administration issued a safety communication as a proposed IV, we estimated IV and propensity score-weighted 2-year risk differences (RDs) using Medicare data (2008-2014). We (i) performed inequality tests, (ii) identified the negative control IV/outcome using causal assumptions, (iii) estimated RDs after narrowing the calendar time range and excluding patients likely associated with unmeasured confounding, (iv) derived bounds for RDs, and (v) estimated the proportion of compliers and their characteristics. The findings revealed that IV assumptions were violated and RDs were extreme, but the assumptions became more plausible upon narrowing the calendar time range and restricting the cohort by excluding prevalent heart failure (the strongest measured predictor of outcome). Systematically evaluating IV assumptions could help detect bias in IV estimators and increase their validity.

Updating and calibrating the Real-World Progression In Diabetes (RAPIDS) model in a non-Veterans Affairs population.

OBJECTIVES: To present the Real-World Progression In Diabetes (RAPIDS) 2.0 Risk Engine, the only simulation model to study the long-term trajectories of outcomes arising from dynamic sequences of glucose-lowering treatments in type 2 diabetes (T2DM). RESEARCH DESIGN AND METHODS: The RAPIDS model's risk equations were re-estimated using a Least Absolute Shrinkage and Selection Operator (LASSO)-based regularization of features that spanned baseline data from the last two quarters of current time and interactions with age. These equations were supplemented with estimates for the impact of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitor classes of drugs as monotherapies and their combinations with metformin based on newer trial data and comprehensive meta-analyses. The probabilistic RAPIDS 2.0 model was calibrated (N = 25 000) and validated (N = 263 816) using electronic medical records (EMR) data between 2008 and 2021 from a national network of US healthcare organizations. RESULTS: The EMR-based cohort had a mean age of 61 years at baseline, with 50% women, 70% non-Hispanic White individuals and 20% non-Hispanic Black individuals, and was followed for 17.5 quarters (range: 3-50). The final RAPIDS 2.0 risk engine accurately predicted the long-term trajectories of all nine biomarkers and nine outcomes in the hold-out validation sample. Similar accuracies in predictions were observed in each of the 14 subgroups studied. CONCLUSION: The RAPIDS 2.0 model demonstrated valid long-term predictions of outcomes in individuals with T2DM in the United States as a function of dynamic sequences of treatment use patterns. This highlights its potential to project long-term comparative effectiveness between alternative sequences of glucose-lowering treatment uses in the United States.

Efficacy and safety of dapagliflozin add-on to evogliptin plus metformin therapy in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled study.

AIM: To evaluate the efficacy and safety of dapagliflozin versus placebo as an add-on in patients with type 2 diabetes who did not achieve adequate glycaemic control with evogliptin and metformin combination. PATIENTS AND METHODS: In this multicentre, randomized, double-blind, placebo-controlled Phase 3 trial, patients with glycated haemoglobin (HbA1c) levels ≥7.0% (≥53 mmol/mol) and ≤10.5% (≤91 mmol/mol) who had received stable-dose metformin (≥1000 mg) and evogliptin (5 mg) for at least 8 weeks were randomized to receive dapagliflozin 10 mg or placebo once daily for 24 weeks. Participants continued treatment with metformin and evogliptin. The primary endpoint was change in HbA1c level after 24 weeks of treatment from baseline level. RESULTS: In total, 198 patients were randomized, and 195 patients were included in the efficacy analyses (dapagliflozin: 96, placebo: 99). At Week 24, dapagliflozin significantly reduced HbA1c levels. The least squares mean difference in HbA1c level change from baseline after 24 weeks of treatment was -0.70% (-7.7 mmol/mol) (p < 0.0001). The proportion of participants achieving HbA1c <7.0% (≥53 mmol/mol) was higher in the dapagliflozin group than in the placebo group. Compared to placebo, dapagliflozin significantly reduced fasting plasma glucose, mean daily glucose, 2-h postprandial plasma glucose, fasting insulin, uric acid and gamma-glutamyl transferase levels, homeostatic model assessment for insulin resistance index, body weight, hepatic steatosis index, and albuminuria. Adiponectin level significantly increased from baseline level after 24 weeks of dapagliflozin treatment. Adverse event rates were similar in the two groups. CONCLUSION: Dapagliflozin add-on to evogliptin plus metformin improved glycaemic control and was well tolerated by the target patients.