The role of sodium-glucose co-transporter-2 inhibitors in frail older adults with or without type 2 diabetes mellitus.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors offer significant outcome benefits beyond glucose lowering, including reduced risk of cardiovascular death, all-cause mortality, major adverse cardiovascular events, hospitalisations for heart failure and progression of renal disease. Considering these therapeutic effects, minimal incremental risk for hypoglycaemia and simplicity of administration, this drug class appears to be an attractive therapeutic option for older adults, and post hoc analysis of trial data provides support for the use of SGLT2 inhibitors in this population. Nevertheless, despite favourable clinical trial data, there has been some hesitance in clinical practice prescribing these drugs to older frail adults due to the limited therapeutic experience in this population and insufficient long-term safety data. In this review article, we evaluate the risk-benefit profile for the use of SGLT2 inhibitors in this population and suggest that rather than being a treatment to avoid, SGLT2 inhibitors should be considered a valid therapeutic option for older frail adults with or without diabetes.

The cost-effectiveness of dapagliflozin in treating high-risk patients with type 2 diabetes mellitus: An economic evaluation using data from the DECLARE-TIMI 58 trial.

AIM: To undertake a cost-effectiveness analysis of dapagliflozin in treating high-risk patients with type 2 diabetes mellitus (T2DM), using both directly observed events in the DECLARE-TIMI 58 trial and surrogate risk factors to predict endpoints not captured within the trial. METHODS: An established T2DM model was adapted to integrate survival curves derived from the DECLARE-TIMI 58 trial, and extrapolated over a lifetime for all-cause mortality, hospitalization for heart failure, stroke, myocardial infarction, hospitalization for unstable angina, and end-stage kidney disease. The economic analysis considered the overall DECLARE trial population, as well as reported patient subgroups. Total and incremental costs, life-years and quality-adjusted life-years associated with dapagliflozin versus placebo were estimated from the perspective of the UK healthcare payer. RESULTS: In the UK setting, treatment with dapagliflozin compared to placebo was estimated to be dominant, with an expected increase in quality-adjusted life-years from 10.43 to 10.48 (+0.06) and a reduction in lifetime total costs from £39 451 to £36 899 (-£2552). Across all patient subgroups, dapagliflozin was estimated to be dominant, with the greatest absolute benefit in the prior heart failure subgroup (incremental lifetime costs -£4150 and quality-adjusted life-years +0.11). CONCLUSIONS: The results of this study demonstrate that dapagliflozin compared to placebo appears to be cost-effective, when considering evidence reported from the DECLARE-TIMI 58 trial, at established UK willingness-to-pay thresholds. The findings highlight the potential of dapagliflozin to have a meaningful impact in reducing the economic burden of T2DM and its associated complications across a broad T2DM population.

Inflammatory biomarkers in Alzheimer's disease plasma.

INTRODUCTION: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a "Holy Grail" of AD research and intensively sought; however, there are no well-established plasma markers. METHODS: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. RESULTS: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOε4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). DISCUSSION: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation.

Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay.

INTRODUCTION: Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins. METHODS: 4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid. RESULTS: A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization. DISCUSSION: The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.

Differential effects of two probiotics on the risks of eczema and atopy associated with single nucleotide polymorphisms to Toll-like receptors.

BACKGROUND: There is strong evidence to support a genetic predisposition to eczema and more recently studies have suggested that probiotics might be used to prevent eczema by modifying the expression of putative allergy-associated genes. The aim of this present study was to investigate whether two probiotics, Lactobacillus rhamnosus HN001 (HN001) and Bifidobacterium animalis subsp. lactis HN019 (HN019), can modify the known genetic predisposition to eczema conferred by genetic variation in the Toll-like receptor (TLR) genes in a high-risk infant population. METHODS: We selected 54 SNPs in the Toll-like receptor genes. These SNPs were analysed in 331 children of sole European ancestry as part of a double-blind, randomized, placebo-controlled trial examining the effects of HN001 and HN019 supplementation on eczema development and atopic sensitization. RESULTS: The data showed that 26 TLR SNPs interacted with HN001 resulting in a significantly reduced risk of eczema, 18 for eczema severity as defined by SCORAD ≥ 10 and 20 for atopic sensitization compared to placebo. There were only two SNPs that interacted with HN019 resulting in a reduced risk of eczema, eczema severity or atopy. CONCLUSIONS: This is the first study to show that the negative impact of specific TLR genotypes may be positively affected by probiotic supplementation. HN001 exhibits a much stronger effect than HN019 in this respect.

Reduced genetic influence on childhood obesity in small for gestational age children.

BACKGROUND: Children born small-for-gestational-age (SGA) are at increased risk of developing obesity and metabolic diseases later in life, a risk which is magnified if followed by accelerated postnatal growth. We investigated whether common gene variants associated with adult obesity were associated with increased postnatal growth, as measured by BMI z-score, in children born SGA and appropriate for gestational age (AGA) in the Auckland Birthweight Collaborative. METHODS: A total of 37 candidate SNPs were genotyped on 547 European children (228 SGA and 319 AGA). Repeated measures of BMI (z-score) were used for assessing obesity status, and results were corrected for multiple testing using the false discovery rate. RESULTS: SGA children had a lower BMI z-score than non-SGA children at assessment age 3.5, 7 and 11 years. We confirmed 27 variants within 14 obesity risk genes to be individually associated with increasing early childhood BMI, predominantly in those born AGA. CONCLUSIONS: Genetic risk variants are less important in influencing early childhood BMI in those born SGA than in those born AGA, suggesting that non-genetic or environmental factors may be more important in influencing childhood BMI in those born SGA.

A consensus viewpoint on the role of direct factor Xa inhibitors in the management of cancer-associated venous thromboembolism in the UK.

OBJECTIVE: Cancer patients are at high risk of venous thromboembolism (VTE), a significant cause of cancer-related death. Historically, low molecular weight heparins (LMWH) were the gold standard therapy for cancer-associated VTE, but recent evidence supports the use of direct factor Xa inhibitors in cancer-associated VTE and this is now reflected in many guidelines. However, uptake of direct factor Xa inhibitors varies and guidance on the use of direct factor Xa inhibitors in specific cancer sub-populations and clinical situations is lacking. This review presents consensus expert opinion alongside evaluation of evidence to support healthcare professionals in the use of direct factor Xa inhibitors in cancer-associated VTE. METHODS: Recent guidelines, meta-analyses, reviews and clinical studies on anticoagulation therapy for cancer-associated VTE were used to direct clinically relevant topics and evidence to be systematically discussed using nominal group technique. The consensus manuscript and recommendations were developed based on these discussions. RESULTS: Considerations when prescribing anticoagulant therapy for cancer-associated VTE include cancer site and stage, systemic anti-cancer therapy (including vascular access), drug-drug interactions, length of anticoagulation, quality of life and needs during palliative care. Treatment of patients with kidney or liver impairment, gastrointestinal disorders, extremes of bodyweight, elevated bleeding or recurrence risk, VTE recurrence and COVID-19 is discussed. CONCLUSION: Anticoagulant therapy for cancer-associated VTE patients should be carefully selected with consideration given to the relative benefits of specific drugs when individualizing care. Direct factor Xa inhibitors are typically the treatment of choice for preventing VTE recurrence in non-cancer patients and should also be considered as such for cancer-associated VTE in most situations.

Determining genetic risk factors for pediatric type 2 diabetes.

The prevalence of type 2 diabetes (T2D) is increasing significantly in the pediatric population. A strong family history of the disease suggests the involvement of genetic factors for diabetes development, but defining the molecular genetics of T2D in children is difficult due to a low number of subjects and the lack of robust diagnostic criteria. Thus, genetic studies of T2D have been carried out almost exclusively in adults. In this review, the genetics of T2D is summarized and options for discovering the missing heritability explored. The review concludes with a discussion of future research that will be required for determining genetic risk factors for pediatric T2D.

The catechol-O-methyltransferase (COMT) Val158Met polymorphism moderates the effect of antenatal stress on childhood behavioural problems: longitudinal evidence across multiple ages.

AIM: The functional polymorphism Val158Met in the catechol-O-methyltransferase (COMT) gene was analysed to determine its association with maternal stress and childhood total difficulties. METHOD: Data were collected at birth from a group of infants who were born small for gestational age and a group who were born at an appropriate size for gestational age and had been enrolled in the Auckland Birthweight Collaborative Study. Children were followed up at the ages of 1 year, 3 years 6 months, 7 years, and 11 years. At the age of 11 years, DNA samples were collected from 546 children (270 females, 276 males): 227 children born small for gestational age and 319 children born at an appropriate size for gestational age. The main independent variable was perceived maternal stress at birth and at 7 and 11 years of age, assessed using the total difficulties scale of the Strength and Difficulties Questionnaire. IQ was assessed at the age of 7 years. RESULTS: Met/Met homozygotes were at a significantly increased risk of behavioural and emotional problems at the ages of 7 (p=0.002) and 11 years (p=0.003), relative to either heterozygous or homozygous carriers of the Val158Met polymorphism, but only when they were exposed to maternal stress in utero. Met/Met homozygotes had, on average, IQ scores that were four points higher than those of Val/Val homozygotes (p=0.010). INTERPRETATION: These findings emphasize the potential long-term consequences of prenatal stress for genetically susceptible individuals during neurodevelopment in utero. Our findings add to the general understanding of the aetiology and developmental nature of childhood emotional and behavioural problems.

Metallothionein genes: no association with Crohn's disease in a New Zealand population.

Metallothioneins (MTs) are excellent candidate genes for Inflammatory Bowel Disease (IBD) and have previously been shown to have altered expression in both animal and human studies of IBD. This is the first study to examine genetic variants within the MT genes and aims to determine whether such genetic variants have an important role in this disease. 28 tag SNPs in genes MT1 (subtypes A, B, E, F, G, H, M, X), MT2, MT3 and MT4 were selected for genotyping in a well-characterized New Zealand dataset consisting of 406 patients with Crohn's Disease and 638 controls. We did not find any evidence of association for MT genetic variation with CD. The lack of association indicates that genetic variants in the MT genes do not play a significant role in predisposing to CD in the New Zealand population.

Cardiorenal disease in the United States: Future health care burden and potential impact of novel therapies.

BACKGROUND: Currently, concerted efforts to identify, prevent, and treat type 2 diabetes mellitus (T2DM), heart failure (HF), and chronic kidney disease (CKD) comorbidities are lacking at the institutional level, with emphasis placed on individual specialties. An integrated approach to tackle T2DM, HF, and CKD within the context of cardiorenal disease has the potential to improve outcomes and reduce costs at the system level. OBJECTIVE: To synthesize published evidence describing the burden of those diagnosed with T2DM, HF, and CKD in the United States as individual discrete chronic conditions, in order to evaluate the potential economic impact of novel therapies in this population. METHODS: We developed a compartmental Markov model with an annual time cycle to model an evolving prevalent US patient population with T2DM, HF, or CKD over the period 2021-2030 (either in isolation or combined). The model was used to explore the potential impact of novel therapies such as sodium-glucose cotransporter 2 inhibitors on future disease burden, by extrapolating the results of relevant clinical trials to representative patient populations. RESULTS: The model estimates that total prevalence across all disease states will have increased by 28% in 2030. Cumulatively, the direct health care cost of cardiorenal disease between 2021 and 2030 is estimated at $4.8 trillion. However, treatment with dapagliflozin has the potential to reduce disease prevalence by 8.0% and estimated cumulative service delivery costs by 3.6% by 2030. CONCLUSIONS: Considering a holistic approach when managing patients with cardiorenal disease offers an opportunity to reduce the disease burden over the next 10 years in the US population. DISCLOSURES: This work was funded by AstraZeneca, which provided support for data analysis. McEwan, Morgan, and Boyce are employees of Health Economics and Outcomes Research Ltd., Cardiff, UK, which received fees from AstraZeneca in relation to this study. Song and Huang are employees of AstraZeneca. Bergenheim is an employee of AstraZeneca and holds AstraZeneca stocks/stock options. Green has no conflicts of interest to declare.

The Population-Wide Risk-Benefit Profile of Extending the Primary COVID-19 Vaccine Course Compared with an mRNA Booster Dose Program.

The vaccination program is reducing the burden of COVID-19. However, recently, COVID-19 infections have been increasing across Europe, providing evidence that vaccine efficacy is waning. Consequently, booster doses are required to restore immunity levels. However, the relative risk-benefit ratio of boosters, compared to pursuing a primary course in the unvaccinated population, remains uncertain. In this study, a susceptible-exposed-infectious-recovered (SEIR) transmission model of SARS-CoV-2 was used to investigate the impact of COVID-19 vaccine waning on disease burden, the benefit of a booster vaccine program compared to targeting the unvaccinated population, and the population-wide risk-benefit profile of vaccination. Our data demonstrates that the rate of vaccine efficacy waning has a significant impact on COVID-19 hospitalisations with the greatest effect in populations with lower vaccination coverage. There was greater benefit associated with a booster vaccination strategy compared to targeting the unvaccinated population, once >50% of the population had received their primary vaccination course. The population benefits of vaccination (reduced hospitalisations, long-COVID and deaths) outweighed the risks of myocarditis/pericarditis by an order of magnitude. Vaccination is important in ending the COVID-19 pandemic sooner, and the reduction in hospitalisations, death and long-COVID associated with vaccination significantly outweigh any risks. Despite these obvious benefits some people are vaccine reluctant, and as such remain unvaccinated. However, when most of a population have been vaccinated, a focus on a booster vaccine strategy for this group is likely to offer greater value, than targeting the proportion of the population who choose to remain unvaccinated.

New Therapeutic Horizons in Chronic Kidney Disease: The Role of SGLT2 Inhibitors in Clinical Practice.

Chronic kidney disease (CKD) is a serious, progressive condition associated with significant patient morbidity. Hypertension control and use of renin-angiotensin system blockers are the cornerstones of treatment for CKD. However, even with these treatment strategies, many individuals will progress towards kidney failure. Recently, sodium-glucose cotransporter 2 (SGLT2) inhibitor clinical trials with primary renal endpoints have firmly established SGLT2 inhibition, in addition to standard of care, as an effective strategy to slow down the progression of CKD and reduce some of its associated complications. The emergence of this new clinical evidence supports the use of SGLT2 inhibitors in the management of CKD in people with and without diabetes. As licensing and guidelines for SGLT2 inhibitors are updated, there is a need to adapt CKD treatment pathways and for this class of drugs to be included as part of standard care for CKD management. In this article, we have used consensus opinion alongside the available evidence to provide support for the healthcare community involved in CKD management, regarding the role of SGLT2 inhibitors in clinical practice. By highlighting appropriate prescribing and practical considerations, we aim to encourage greater and safe use of SGLT2 inhibitors for people with CKD, both with and without diabetes.

Meeting the Challenge of Virtual Diabetes Care: A Consensus Viewpoint on the Positioning and Value of Oral Semaglutide in Routine Clinical Practice.

While glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, are among the most effective drugs for treating people with type 2 diabetes (T2D), they are clinically under-utilised. Until recently, the only route for semaglutide administration was via subcutaneous injection. However, an oral formulation of semaglutide was recently licensed, with the potential to address therapy inertia and increase patient adherence to treatment, which is essential in controlling blood glucose and reducing complications. The availability of oral semaglutide provides a new option for both clinicians and patients who are reluctant to use an injectable agent. This has been of particular importance in addressing the challenge of virtual diabetes care during the COVID-19 pandemic, circumventing the logistical problems that are often associated with subcutaneous medication administration. However, there remains limited awareness of the clinical and economic value of oral semaglutide in routine clinical practice. In this article, we present our consensus opinion on the role of oral semaglutide in routine clinical practice and discuss its value in reducing the burden of delivering diabetes care in the post-COVID-19 pandemic period of chronic disease management.

Defining the Role of SGLT2 Inhibitors in Primary Care: Time to Think Differently.

Disease burden in people with diabetes is mainly driven by long-term complications such as cardiovascular disease, heart failure and chronic kidney disease. This is a consequence of the interconnection between the cardiovascular, renal and metabolic systems, through a continuous chain of events referred to as 'the cardiorenal metabolic continuum'. Increasing evidence suggests that sodium-glucose cotransporter 2 inhibitors (SGLT2is) have beneficial effects across all stages of the cardiorenal metabolic continuum, reducing morbidity and mortality in a wide range of individuals, from those with diabetes and multiple risk factors to those with established heart failure and chronic kidney disease, regardless of the presence of diabetes. Despite this robust evidence base, the complexity of label indications and misconceptions concerning potential side effects have resulted in a lack of clear understanding in primary care regarding the implementation of SGLT2is in clinical practice. With this in mind, we provide an overview of the clinical and economic benefits of SGLT2is across the cardiorenal metabolic continuum together with practical considerations in order to help address some of these concerns and clearly define the role of SGLT2is in primary care as a holistic outcomes-driven treatment with the potential to reduce disease burden across the cardiorenal metabolic spectrum.

A Narrative Review of Chronic Kidney Disease in Clinical Practice: Current Challenges and Future Perspectives.

Chronic kidney disease (CKD) is a complex disease which affects approximately 13% of the world's population. Over time, CKD can cause renal dysfunction and progression to end-stage kidney disease and cardiovascular disease. Complications associated with CKD may contribute to the acceleration of disease progression and the risk of cardiovascular-related morbidities. Early CKD is asymptomatic, and symptoms only present at later stages when complications of the disease arise, such as a decline in kidney function and the presence of other comorbidities associated with the disease. In advanced stages of the disease, when kidney function is significantly impaired, patients can only be treated with dialysis or a transplant. With limited treatment options available, an increasing prevalence of both the elderly population and comorbidities associated with the disease, the prevalence of CKD is set to rise. This review discusses the current challenges and the unmet patient need in CKD.

One Hundred Years of Insulin: Value Beyond Price in Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus is a chronic, progressive disease that frequently necessitates treatment with basal insulin to maintain adequate glycaemic control. In considering the value of different basal insulin therapies, although acquisition costs are of increasing importance to budget-constrained healthcare systems, value beyond simple price considerations should be taken into account. Whilst human basal insulins are of lower acquisition cost compared to long-acting insulin analogues, this difference in price has the potential to be offset in terms of total healthcare system value through the ultra-long duration of action and low variability in glucose-lowering activity which have been translated into real clinical benefits, in particular a reduced risk of hypoglycaemic events. The maintenance of glycaemic targets and avoidance of hypoglycaemia that have been associated with insulin analogues represent a significant value consideration, beyond price, for the use of basal insulin analogues to manage type 2 diabetes mellitus from the perspective of all stakeholders within the healthcare system, including payers, healthcare professionals, patients and society.

The Value of Insulin Degludec in Frail Older Adults with Type 2 Diabetes.

Insulin represents a mainstay of glucose-lowering therapy for many adults with type 2 diabetes mellitus (T2DM). Insulin treatments prescribed as standard care for the majority of people with T2DM, such as basal human insulin, may not be optimal in the treatment of frail older adults because of the increased demand on health care staff to administer multiple daily injections and monitor the patient. When choosing an insulin regimen for a frail older person with T2DM, predictability of glucose lowering effect, risk of hypoglycaemia, ease of administration, and simplicity and flexibility of dosing are major determining factors. Multiple daily injections may be too complex for older frail adults, whilst providing an unnecessary degree of tight glycaemic control and low doses of once-daily basal insulin analogues such as insulin degludec may be a reasonable option as cognitive decline or functional disability increases. Although insulin degludec has a substantially higher acquisition cost than routinely used basal human insulin, it has a longer, more predictable pharmacological profile and is more amenable to once-daily administration, translating into a reduced burden of care and potential cost savings for insulin-treated frail older adults. Insulin acquisition cost represents only a small proportion of the total cost of treatment, and it is important to consider the value perspective of insulin therapy in frail older adults from all stakeholders in the health care system.

Vaccinating Adolescents and Children Significantly Reduces COVID-19 Morbidity and Mortality across All Ages: A Population-Based Modeling Study Using the UK as an Example.

Debate persists around the risk-benefit balance of vaccinating adolescents and children against COVID-19. Central to this debate is quantifying the contribution of adolescents and children to the transmission of SARS-CoV-2, and the potential impact of vaccinating these age groups. In this study, we present a novel SEIR mathematical disease transmission model that quantifies the impact of different vaccination strategies on population-level SARS-CoV-2 infections and clinical outcomes. The model employs both age- and time-dependent social mixing patterns to capture the impact of changes in restrictions. The model was used to assess the impact of vaccinating adolescents and children on the natural history of the COVID-19 pandemic across all age groups, using the UK as an example. The base case model demonstrates significant increases in COVID-19 disease burden in the UK following a relaxation of restrictions, if vaccines are limited to those ≥18 years and vulnerable adolescents (≥12 years). Including adolescents and children in the vaccination program could reduce overall COVID-related mortality by 57%, and reduce cases of long COVID by 75%. This study demonstrates that vaccinating adolescents and children has the potential to play a vital role in reducing SARS-CoV-2 infections, and subsequent COVID-19 morbidity and mortality, across all ages. Our results have major global public health implications and provide valuable information to inform a potential pandemic exit strategy.

Optimising the Heart Failure Treatment Pathway: The Role of SGLT2 Inhibitors.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were first developed as glucose-lowering therapies for the treatment of diabetes. However, these drugs have now been recognised to prevent worsening heart-failure events, improve health-related quality of life, and reduce mortality in people with heart failure with reduced ejection fraction (HFrEF), including those both with and without diabetes. Despite robust clinical trial data demonstrating favourable outcomes with SGLT2 inhibitors for patients with HFrEF, there is a lack of familiarity with the HF indication for these drugs, which have been the remit of diabetologists to date. In this article we use consensus expert opinion alongside the available evidence and label indication to provide support for the healthcare community treating people with HF regarding positioning of SGLT2 inhibitors within the treatment pathway. By highlighting appropriate prescribing and practical considerations, we hope to encourage greater, and safe, use of SGLT2 inhibitors in this population.