Perioperative use of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors for diabetes mellitus.

Type 2 diabetes mellitus is an increasingly common long-term condition, and suboptimal perioperative glycaemic control can lead to postoperative harms. The advent of new antidiabetic drugs, in particular glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, has enabled perioperative continuation of these medicines, thus avoiding the harms of variable rate i.v. insulin infusions whilst providing glycaemic control. There are differences between medicines regulatory agencies and organisations on how these classes that are most often used to treat diabetes mellitus, (but also in the case of SGLT2 inhibitors chronic kidney disease and heart failure in those without diabetes) should be managed in the perioperative period. In this commentary, we argue that GLP-1 receptor agonists should continue during the perioperative period and that SGLT2 inhibitors should only be omitted the day prior to a planned procedure . The reasons for the differing advice advocated between regulatory agencies and what anaesthetic practitioners should do in the face of continuing uncertainty are discussed.

Management of Hyperosmolar Hyperglycaemic State (HHS) in Adults: An updated guideline from the Joint British Diabetes Societies (JBDS) for Inpatient Care Group.

Hyperosmolar Hyperglycaemic State (HHS) is a medical emergency associated with high mortality. It occurs less frequently than diabetic ketoacidosis (DKA), affects those with pre-existing/new type 2 diabetes mellitus and increasingly affecting children/younger adults. Mixed DKA/HHS may occur. The JBDS HHS care pathway consists of 3 themes (clinical assessment and monitoring, interventions, assessments and prevention of harm) and 5 phases of therapy (0-60 min, 1-6, 6-12, 12-24 and 24-72 h). Clinical features of HHS include marked hypovolaemia, osmolality ≥320 mOsm/kg using [(2×Na+ ) + glucose+urea], marked hyperglycaemia ≥30 mmol/L, without significant ketonaemia (≤3.0 mmol/L), without significant acidosis (pH >7.3) and bicarbonate ≥15 mmol/L. Aims of the therapy are to improve clinical status/replace fluid losses by 24 h, gradual decline in osmolality (3.0-8.0 mOsm/kg/h to minimise the risk of neurological complications), blood glucose 10-15 mmol/L in the first 24 h, prevent hypoglycaemia/hypokalaemia and prevent harm (VTE, osmotic demyelination, fluid overload, foot ulceration). Underlying precipitants must be identified and treated. Interventions include: (1) intravenous (IV) 0.9% sodium chloride to restore circulating volume (fluid losses 100-220 ml/kg, caution in elderly), (2) fixed rate intravenous insulin infusion (FRIII) should be commenced once osmolality stops falling with fluid replacement unless there is ketonaemia (FRIII should be commenced at the same time as IV fluids). (3) glucose infusion (5% or 10%) should be started once glucose <14 mmol/L and (4) potassium replacement according to potassium levels. HHS resolution criteria are: osmolality <300 mOsm/kg, hypovolaemia corrected (urine output ≥0.5 ml/kg/h), cognitive status returned to pre-morbid state and blood glucose <15 mmol/L.

GLP-1 receptor agonist use during hospitalisation: Better glycaemic control compared to premixed insulin.

INTRODUCTION: Glycaemic control associates with better outcomes for hospitalised patients. Whether GLP-1 receptor agonists (GLP-1 RA) are suitable and effective drugs for inpatients is unclear. METHODS: A retrospective, single centre, observational study using data from the electronic health record. Patients admitted using GLP-1 RA as outpatients, from 2016 to 2019, were identified. Outcomes were compared to those admitted using twice-daily (BD) mixed insulin. Capillary glucose, medication use, creatinine, and demographic data were collected. As drugs may be discontinued/not administered in hospital, days when GLP-1 RA was administered were 'GLP-1 RA active' and, for insulin, 'insulin active'. The primary comparison was rate of hypoglycaemia (<4 mmol/L) and severe hypoglycaemia (<3 mmol/L). A logistic regression model examined variables for hypoglycaemia. RESULTS: GLP-1 RA comprised n = 262 admissions and BD insulin n = 166. The 'insulin active' cohort (n = 957 patient days) had higher risk of hypoglycaemia than 'GLP-1 RA active' (n = 806 days); occurring on 14.7% of days; 95% confidence interval [CI] 12.6-17.1 versus 9.9% days; 95% CI 8.0-12.2; p = 0.002, and severe hypoglycaemia 4.0% of days (95% CI 2.8-5.4) versus 2.0% (95% CI 1.1%-3.2%; p = 0.005). Daily glucose (mean ± standard deviation) was 10.8 ± 5.2 mmol/L in insulin active versus 9.6 ± 4.7 mmol/L in GLP-1 RA active; p < 0.001. Insulin use, age, and acute admissions predicted hypoglycaemia. The odds ratio for hypoglycaemia was 2.15 times greater (95% CI, 1.14-4.08; p = 0.019) with insulin than with GLP-1 RA. CONCLUSIONS: GLP-1 RA provided better glycaemic control than BD mixed insulin and should be continued during hospitalisation unless there is a clear indication for cessation.

An implementation framework and a feasibility evaluation of a clinical decision support system for diabetes management in secondary mental healthcare using CogStack.

BACKGROUND: Improvements to the primary prevention of physical health illnesses like diabetes in the general population have not been mirrored to the same extent in people with serious mental illness (SMI). This work evaluates the technical feasibility of implementing an electronic clinical decision support system (eCDSS) for supporting the management of dysglycaemia and diabetes in patients with serious mental illness in a secondary mental healthcare setting. METHODS: A stepwise approach was taken as an overarching and guiding framework for this work. Participatory methods were employed to design and deploy a monitoring and alerting eCDSS. The eCDSS was evaluated for its technical feasibility. The initial part of the feasibility evaluation was conducted in an outpatient community mental health team. Thereafter, the evaluation of the eCDSS progressed to a more in-depth in silico validation. RESULTS: A digital health intervention that enables monitoring and alerting of at-risk patients based on an approved diabetes management guideline was developed. The eCDSS generated alerts according to expected standards and in line with clinical guideline recommendations. CONCLUSIONS: It is feasible to design and deploy a functional monitoring and alerting eCDSS in secondary mental healthcare. Further work is required in order to fully evaluate the integration of the eCDSS into routine clinical workflows. By describing and sharing the steps that were and will be taken from concept to clinical testing, useful insights could be provided to teams that are interested in building similar digital health interventions.

Neutrophil-endothelial interactions of murine cells is not a good predictor of their interactions in human cells.

All drugs recently developed in rodent models to treat inflammatory disease have failed in clinical trials. We therefore used our novel biomimetic microfluidic assay (bMFA) to determine whether the response of murine cells to inflammatory activation or anti-inflammatory treatment is predictive of the response in human cells. Under physiologically relevant flow conditions, permeability and transendothelial electrical resistance (TEER) of human or mouse lung microvascular endothelial cells (HLMVEC or MLMVEC), and neutrophil-endothelial cell interaction was measured. The differential impact of a protein kinase C-delta TAT peptide inhibitor (PKCδ-i) was also quantified. Permeability of HLMVEC and MLMVEC was similar under control conditions but tumor necrosis factor α (TNF-α) and PKCδ-i had a significantly higher impact on permeability of HLMVEC. TEER across HLMVEC was significantly higher than MLMVEC, but PKCδ-i returned TEER to background levels only in human cells. The kinetics of N-formylmethionyl-leucyl-phenylalanine (fMLP)-mediated neutrophil migration was significantly different between the two species and PKCδ-i was significantly more effective in attenuating human neutrophil migration. However, human and mouse neutrophil adhesion patterns to microvascular endothelium were not significantly different. Surprisingly, while intercellular adhesion molecule 1 (ICAM-1) was significantly upregulated on activated HLMVEC, it was not significantly upregulated on activated MLMVEC. Responses to activation and anti-inflammatory treatment in mice may not always be predictive of their response in humans.

The use of sodium-glucose co-transporter 2 inhibitors in the inpatient setting: Is the risk worth taking?

WHAT IS KNOWN AND OBJECTIVE: In the outpatient setting, sodium-glucose co-transporter 2 inhibitors (SGLT2i) are recognized as effective agents to optimize glycaemia and also developing robust evidence for cardiovascular (CV) and renal protection in people with type 2 diabetes, particularly those at higher risk. However, data on the safety and efficacy of these drugs in hospitalized patients remain limited. The purpose of this review is to discuss the balance between risks and benefits of SGLT2i use in the inpatient setting. METHODS: PubMed, Embase and Google Scholar databases were searched to identify relevant published work. Available evidence on the mechanisms of action and the safety profile of SGLT2i in the context of their use in hospitalized individuals are summarized and discussed in this narrative review. RESULTS AND DISCUSSION: The rationale behind the use of these agents in the inpatient setting is based on the low risk of hypoglycaemia, the practical dosing scheme and the potential to decrease subsequent heart failure admission rates. In addition, data from animal studies indicate the ability of SGLT2i to ameliorate oxidative stress, suppress sympathetic activity, enhance autophagy and promote cardiac remodelling, when administered in the acute phase of CV episodes. On the other hand, these drugs have been linked to specific adverse events related to their mechanism of action, including an increased risk of euglycaemic diabetic ketoacidosis and volume depletion, which raises concerns over their usefulness in inpatients, particularly individuals with multimorbidities. WHAT IS NEW AND CONCLUSION: Potential benefits deriving from the use of SGLT2i in the inpatient setting cannot mitigate possible risks, at least until robust evidence on their efficacy in hospitalized individuals become available. The concept of administering these agents in the acute phase of CV episodes, in people with or without diabetes, requires further evaluation in appropriately designed clinical studies.

The use of GLP-1 receptor agonists in hospitalised patients: An untapped potential.

In the outpatient setting, glucagon-like peptide-1 (GLP-1) receptor agonists have proved to be highly efficacious drugs that provide glycaemic control with a low risk of hypoglycaemia. These characteristics make GLP-1 receptor agonists attractive agents to treat dysglycaemia in perioperative or high-dependency hospital settings, where glycaemic variability and hyperglycaemia are associated with poor prognosis. GLP-1 also has a direct action on the myocardium and vasculature-which may be advantageous in the immediate aftermath of a vascular insult. This is a narrative review of the work in this area. The aim was to determine the populations of hospitalised patients being evaluated and the clinical and mechanistic end-points tested, with the institution of GLP-1 therapy in hospital. We searched the PubMed, Embase, and Google scholar databases, combining the term "glucagon-like peptide 1" OR "GLP-1" OR "incretin" OR "liraglutide" OR "exenatide" OR "lixisenatide" OR "dulaglutide" OR "albiglutide" AND "inpatient" OR "hospital" OR "perioperative" OR "postoperative" OR "surgery" OR "myocardial infarction" OR "stroke" OR "cerebrovascular disease" OR "transient ischaemic attack" OR "ICU" OR "critical care" OR "critical illness" OR "CCU" OR "coronary care unit." Pilot studies were reported in the fields of acute stroke, cardiac resuscitation, coronary care, and perioperative care that showed advantages for GLP-1 therapy, with normalisation of glucose, lower glucose variability, and lower risk of hypoglycaemia. Animal and human studies have reported improvements in myocardial performance when given acutely after vascular insult or surgery, but these have yet to be translated into randomised clinical trials.

Implementation of an Electronic Clinical Decision Support System for the Early Recognition and Management of Dysglycemia in an Inpatient Mental Health Setting Using CogStack: Protocol for a Pilot Hybrid Type 3 Effectiveness-Implementation Randomized Controlled Cluster Trial.

BACKGROUND: Severe mental illnesses (SMIs), including schizophrenia, bipolar affective disorder, and major depressive disorder, are associated with an increased risk of physical health comorbidities and premature mortality from conditions including cardiovascular disease and diabetes. Digital technologies such as electronic clinical decision support systems (eCDSSs) could play a crucial role in improving the clinician-led management of conditions such as dysglycemia (deranged blood sugar levels) and associated conditions such as diabetes in people with a diagnosis of SMI in mental health settings. OBJECTIVE: We have developed a real-time eCDSS using CogStack, an information retrieval and extraction platform, to automatically alert clinicians with National Health Service Trust-approved, guideline-based recommendations for dysglycemia monitoring and management in secondary mental health care. This novel system aims to improve the management of dysglycemia and associated conditions, such as diabetes, in SMI. This protocol describes a pilot study to explore the acceptability, feasibility, and evaluation of its implementation in a mental health inpatient setting. METHODS: This will be a pilot hybrid type 3 effectiveness-implementation randomized controlled cluster trial in inpatient mental health wards. A ward will be the unit of recruitment, where it will be randomly allocated to receive either access to the eCDSS plus usual care or usual care alone over a 4-month period. We will measure implementation outcomes, including the feasibility and acceptability of the eCDSS to clinicians, as primary outcomes, alongside secondary outcomes relating to the process of care measures such as dysglycemia screening rates. An evaluation of other implementation outcomes relating to the eCDSS will be conducted, identifying facilitators and barriers based on established implementation science frameworks. RESULTS: Enrollment of wards began in April 2022, after which clinical staff were recruited to take part in surveys and interviews. The intervention period of the trial began in February 2023, and subsequent data collection was completed in August 2023. Data are currently being analyzed, and results are expected to be available in June 2024. CONCLUSIONS: An eCDSS can have the potential to improve clinician-led management of dysglycemia in inpatient mental health settings. If found to be feasible and acceptable, then, in combination with the results of the implementation evaluation, the system can be refined and improved to support future successful implementation. A larger and more definitive effectiveness trial should then be conducted to assess its impact on clinical outcomes and to inform scalability and application to other conditions in wider mental health care settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT04792268; https://clinicaltrials.gov/study/NCT04792268. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/49548.

GLP-1 Receptor Agonists in Obese Patients with Inflammatory Bowel Disease: from Molecular Mechanisms to Clinical Considerations and Practical Recommendations for Safe and Effective Use.

PURPOSE OF REVIEW: To discuss current literature and provide practical recommendations for the safe and effective use of glucagon-like peptide 1 receptor agonists (GLP-1 RA) in people with inflammatory bowel disease (IBD) and type 2 diabetes (T2D) and/or obesity. The molecular mechanisms that justify the potential benefits of GLP-1 RA in IBD and the links between IBD, obesity, and cardiovascular disease are also discussed. RECENT FINDINGS: Preliminary data suggest that GLP-1 RA can modulate crucial pathways in the pathogenesis of IBD, such as chronic inflammation circuits, intestinal tight junctions, and gut microbiome dysbiosis, setting the stage for human trials to investigate the role of these agents in the treatment of IBD among people with or without diabetes and obesity. However, gastrointestinal side effects related to GLP-1 RA need appropriate clinical management to mitigate risks and maximize the benefits of therapy in people with IBD. GLP-1 RA originally emerged as drugs for the treatment of hyperglycemia and are currently licensed for the management of T2D and/or overweight/obesity. However, their wealth of pleiotropic actions soon raised expectations that they might confer benefits on non-metabolic disorders. Future studies are expected to clarify whether GLP-1 RA deserve an adjunct place in the arsenal of drugs against IBD.

Review of Iraq's nationwide attempts to transform medical school curricula over the last ten decades.

Background: The first medical college in Iraq was established in 1927, adopting a subject-based curriculum. Aims: To provide a description of undergraduate medical education curricula in Iraq and how they developed since 1927. Methods: We identified Iraqi medical schools and curricula from local and global directories. Curricular data were compared to 3 educational benchmarks (Dale's effectiveness of teaching methods, SPICES, Miller's pyramid). We searched for studies describing curricula and modernization. Results: There are 34 medical colleges in Iraq (32 with identified curricula) with a wide scope of visions and aims adopting 3 types of curriculum: subject-based (SBC) 20 (63%), integrated (IC) 10 (31%) and problem-based learning (PBLC) 2 (6%). The majority of updates were SBC to IC, with only 1 moving from SBC to PBLC. The predominant type of curriculum at the start of instruction is SBC or IC. Although PBLC and IC provide opportunities for inquiry-driven competencies in the first 3 years only, none provide such opportunities in the clinical phase (last 3 years). Conclusions: Curricular reform needs to focus on modernizing the learning process/outcomes rather than reorganization of the teaching only. A new approach is needed to provide opportunities for competence and experience to prepare doctors to deal with challenges. One such approach would be the adoption of an outcomes-based curriculum model based on domains of competence with clearly defined outcomes/competencies achievable the time of graduation. All curricula should lead to the achievement of the same outcomes.

From Skepticism to Hope: The Evolving Concept of the Initiation and Use of Sodium-Glucose Cotransporter 2 Inhibitors in Hospitalized Patients.

The management of hyperglycemia in patients admitted to hospital is mainly based on insulin therapy. However, the positive and rapid effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiorenal outcomes raises the possibility that they might confer benefits to hospitalized patients. In recent, well designed, randomized trials (SOLOIST-WHF and EMPULSE) recruiting inpatients with heart failure (HF), SGLT2i demonstrated the potential to improve survival and quality of life and reduce the number of HF events, time to first HF event, hospitalizations, and urgent visits for HF compared with placebo. They were also well tolerated, whereas incidence of diabetic ketoacidosis was low. In EMBODY, empagliflozin was shown to be protective against the deleterious effects of cardiac injury in patients with acute myocardial infarction. In DARE-19, the administration of dapagliflozin to inpatients with cardiometabolic risk factors and COVID-19 was based on the hypothesis that the anti-inflammatory properties of SGLT2i could alleviate organ damage. Although the findings did not reach statistical significance, the efficacy and safety profiles of the drug were encouraging. These promising findings in the field of cardiometabolic medicine set the stage for future research to explore whether the benefits of gliflozins can expand to inpatients with non-cardiometabolic disorders, including sepsis, cirrhotic ascites, and malignancies. The concept of inpatient use of SGLT2i has evolved greatly over the past few years. The latest evidence suggests that SGLT2i may be effective and safe in the hospital setting, provided patients are carefully selected and closely monitored. Real-world data will prove whether present hope about inpatient use of gliflozins will transform into future confidence.

Insights Into the Results of Sotagliflozin Cardiovascular Outcome Trials: Is Dual Inhibition the Cherry on the Cake of Cardiorenal Protection?

Sotagliflozin is a dual sodium-glucose co-transporter (SGLT) 2 inhibitor, manifesting a 20-fold higher inhibitory activity for SGLT2 than for SGLT1. Differences in SGLT2 over SGLT1 selectivity of the available agents have been proposed to relate to variability in efficacy and safety characteristics. In contrast to other SGLT2 inhibitors, the cardiorenal effects of sotagliflozin in type 2 diabetes had not been explored until recently, when the results of SOLOIST-WHF (focusing on heart failure [HF] outcomes) and SCORED (focusing on renal outcomes) were published. In SOLOIST-WHF, sotagliflozin reduced the risk of the primary composite outcome of cardiovascular (CV) death and hospitalizations and urgent visits for HF. The findings showed that the risk reduction was consistent in people with reduced but also in those with preserved ejection fraction (EF). In SCORED, sotagliflozin significantly reduced the primary end point of CV deaths, hospitalizations for HF, and urgent visits for HF. A reduction in glycated hemoglobin was evident even in participants with estimated glomerular filtration rate values below 30 mL/min/1.73 m2. SCORED is also the first trial to illustrate the benefits of the class across the full range of albuminuria. Moreover, the endpoint of stroke was significantly reduced by 34% in the sotagliflozin compared with the placebo group. The findings of the two studies provide novel insights into the clinical utility of SGLT2 inhibitors, particularly with respect to the early initiation in stable HF, the benefits in HF with preserved EF, the glucose-lowering efficacy in people with severe renal impairment and their potential to improve atherosclerotic vascular disease, including stroke, outcomes.

Management of Diabetes in People Undergoing Dental Treatment in Primary Care.

Diabetes mellitus is a condition resulting from loss of production of insulin, or insufficient production/insulin resistance leading to high blood glucose levels. Management of the condition can be provided in a variety of settings and is tailored to the person's requirements. The condition has a lifelong, systemic impact due to microvascular and macrovascular complications. Diabetes mellitus has dental implications due to increased risk of infections, poor wound healing, rapid progression of periapical pathology, xerostomia, burning mouth syndrome, and a bidirectional link with periodontal disease. Two clinical cases of patients with diabetes are discussed and their dental management described. Many people with diabetes can be treated in primary care, however, some with suboptimal glycaemic control may require specialist input and liaison with the patient's diabetes team.

Safe care for people with diabetes in hospital.

Diabetes is the most prevalent long-term condition, occurring in approximately 6.5% of the UK population. However, an average of 18% of all acute hospital beds are occupied by someone with diabetes. Having diabetes in hospital is associated with increased harm - however that may be defined. Over the last few years the groups such as the Joint British Diabetes Societies for Inpatient Care have produced guidelines to help medical and nursing staff manage inpatients with diabetes. These guidelines have been rapidly adopted across the UK. The National Diabetes Inpatient Audit has shown that over the last few years the care for people with diabetes has slowly improved, but there remain challenges in terms of providing appropriate staffing and education. Patient safety is paramount, and thus there remains a lot to do to ensure this vulnerable group of people are not at increased risk of harm.

Into the deep blue sea: A review of the safety of recreational diving in people with diabetes mellitus.

People with diabetes, particularly those being insulin treated, have been for many years considered ineligible for diving, because of the high risk of adverse events. Blood glucose levels tend to decline during diving, probably because of changes in insulin requirements and resistance, due to increased physical activity and effects of hyperbaric environment on glucose tolerance. Strict adherence to safety protocols, in conjunction with optimal physical status, lack of diabetic complications (especially impaired awareness of hypoglycaemia) and satisfactory baseline glycaemic control, seem to minimise the risk of complications during diving. The integration of modern technology into diabetes management, providing potential for underwater continuous glucose monitoring, can be useful in optimising metabolic control before, during and after diving. Despite the significant progress been made on safety issues, there is still a need to implement the relevant recommendations into divers' everyday practice. Existing evidence is mainly derived from small studies and there is a wide heterogeneity in terms of study designs and explored outcomes, rendering the extraction of definitive conclusions challenging. The aim of this review is to present and critically evaluate available evidence, use of technology, and gaps in existing knowledge that deserve further evaluation by future studies.

Anti-incretin effect: The other face of Janus in human glucose homeostasis.

The provocative idea that type 2 diabetes (T2D) may be a surgically treated disorder is based on accumulating evidence suggesting impressive remission rates of obesity and diabetes following bariatric surgery interventions. According to the "anti-incretin" theory, ingestion of food in the gastrointestinal (GI) tract, apart from activating the well-described incretin effect, also results in the parallel stimulation of a series of negative feedback mechanisms (anti-incretin effect). The primary goal of these regulations is to counteract the effects of incretins and other postprandial glucose-lowering adaptive mechanisms. Disruption of the equilibrium between incretins and anti-incretins could be an additional pathway leading to the development of insulin resistance and hyperglycemia. This theory provides an alternative theoretical framework to explain the mechanisms behind the optimal effects of metabolic surgery on T2D and underlines the importance of the GI tract in the homeostatic regulation of energy balance in humans. The anti-incretin concept is currently based on a limited amount of evidence and certainly requires further validation by additional studies. The aim of the present review is to discuss and critically evaluate recent evidence on the anti-incretin theory, providing an insight into current state and future perspectives.

The Effects of High Altitude on Glucose Homeostasis, Metabolic Control, and Other Diabetes-Related Parameters: From Animal Studies to Real Life.

Exposure to high altitude activates several complex and adaptive mechanisms aiming to protect human homeostasis from extreme environmental conditions, such as hypoxia and low temperatures. Short-term exposure is followed by transient hyperglycemia, mainly triggered by the activation of the sympathetic system, whereas long-term exposure results in lower plasma glucose concentrations, mediated by improved insulin sensitivity and augmented peripheral glucose disposal. An inverse relationship between altitude, diabetes, and obesity has been well documented. This is the result of genetic and physiological adaptations principally to hypoxia that favorably affect glucose metabolism; however, the contribution of financial, dietary, and other life-style parameters may also be important. According to existing evidence, people with diabetes are capable of undertaking demanding physical challenges even at extreme altitudes. Still, a number of issues should be taken into account, including the increased physical activity leading to changes in insulin demands and resistance, the performance of measurement systems under extreme weather conditions and the potential deterioration of metabolic control during climbing expeditions. The aim of this review is to present available evidence in the field in a comprehensive way, beginning from the physiology of glucose homeostasis adaptation mechanisms to high altitudes and ending to what real life experience has taught us.