Sodium-glucose Co-transporter 2 Inhibitors: A Novel Molecule for Health Care Practitioners in Diabetology, Cardiology and Nephrology

Prevention and timely management of cardiovascular (CV) complications like myocardial infarction, heart failure (HF), stroke and renal complications, like chronic kidney disease (CKD) and end-stage renal disease, are important to improve the quality of life and survival in people with type 2 diabetes mellitus (T2DM). The multifaceted action of sodium-glucose co-transporter 2 inhibitors (SGLT2i) results in effective glycemic control with benefits on CV and renal risk factors, like body weight, blood pressure, uric acid and albuminuria. Robust CV and renal event reduction is reflected in the outcomes of large CV outcome trials, meta-analyses and real-world studies. Recent evidence has proven cardiac and renal benefits with SGLT2i in subjects with HF and CKD irrespective of their T2DM status. Until recently, SGLT2i was used as a glucose-lowering molecule with pleiotropic benefits, mainly by primary care practitioners and diabetologists. The potential for cardiac and renal protection in people with and without T2DM has shifted an interest in cardiologists and nephrologists to view it as a cardiac and renal molecule, respectively. Thus, the role of SGLT2i in the management of T2DM is undergoing a paradigm shift—straddling the interfaces of diabetology, cardiology, nephrology and primary care—moving away from being considered a pure antidiabetic molecule. We conducted a literature review of SGLT2i in management of T2DM along with their protective effects on CV and renal parameters in patients with or without baseline comorbidities

Sodium-glucose Co-transporter 2 Inhibitors: A Novel Molecule for Health Care Practitioners in Diabetology, Cardiology and Nephrology

Prevention and timely management of cardiovascular (CV) complications like myocardial infarction, heart failure (HF), stroke and renal complications, like chronic kidney disease (CKD) and end-stage renal disease, are important to improve the quality of life and survival in people with type 2 diabetes mellitus (T2DM). The multifaceted action of sodium-glucose co-transporter 2 inhibitors (SGLT2i) results in effective glycemic control with benefits on CV and renal risk factors, like body weight, blood pressure, uric acid and albuminuria. Robust CV and renal event reduction is reflected in the outcomes of large CV outcome trials, meta-analyses and real-world studies. Recent evidence has proven cardiac and renal benefits with SGLT2i in subjects with HF and CKD irrespective of their T2DM status. Until recently, SGLT2i was used as a glucose-lowering molecule with pleiotropic benefits, mainly by primary care practitioners and diabetologists. The potential for cardiac and renal protection in people with and without T2DM has shifted an interest in cardiologists and nephrologists to view it as a cardiac and renal molecule, respectively. Thus, the role of SGLT2i in the management of T2DM is undergoing a paradigm shift—straddling the interfaces of diabetology, cardiology, nephrology and primary care—moving away from being considered a pure antidiabetic molecule. We conducted a literature review of SGLT2i in management of T2DM along with their protective effects on CV and renal parameters in patients with or without baseline comorbidities

Handwashing, sanitation and family planning practices are the strongest underlying determinants of child stunting in rural indigenous communities of Jharkhand and Odisha, Eastern India: a cross-sectional study

The World Health Organisation has called for global action to reduce child stunting by 40% by 2025. One third of the world's stunted children live in India, and children belonging to rural indigenous communities are the worst affected. We sought to identify the strongest determinants of stunting among indigenous children in rural Jharkhand and Odisha, India, to highlight key areas for intervention. We analysed data from 1227 children aged 6–23.99 months and their mothers, collected in 2010 from 18 clusters of villages with a high proportion of people from indigenous groups in three districts. We measured height and weight of mothers and children, and captured data on various basic, underlying and immediate determinants of undernutrition. We used Generalised Estimating Equations to identify individual determinants associated with children's height-for-age z-score (HAZ; p < 0.10); we included these in a multivariable model to identify the strongest HAZ determinants using backwards stepwise methods. In the adjusted model, the strongest protective factors for linear growth included cooking outdoors rather than indoors (HAZ +0.66), birth spacing ≥24 months (HAZ +0.40), and handwashing with a cleansing agent (HAZ +0.32). The strongest risk factors were later birth order (HAZ −0.38) and repeated diarrhoeal infection (HAZ −0.23). Our results suggest multiple risk factors for linear growth faltering in indigenous communities in Jharkhand and Odisha. Interventions that could improve children's growth include reducing exposure to indoor air pollution, increasing access to family planning, reducing diarrhoeal infections, improving handwashing practices, increasing access to income and strengthening health and sanitation infrastructure

A proteomics study of rheumatoid arthritis patients on etanercept identifies putative biomarkers associated with clinical outcome measures

\ua9 The Author(s) 2023. Objectives: Biologic DMARDs (bDMARDs) are widely used in patients with RA, but response to bDMARDs is heterogeneous. The objective of this work was to identify pretreatment proteomic biomarkers associated with RA clinical outcome measures in patients starting bDMARDs. Methods: Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) was used to generate spectral maps of sera from patients with RA before and after 3 months of treatment with the bDMARD etanercept. Protein levels were regressed against RA clinical outcome measures, i.e. 28-joint DAS (DAS28) and its subcomponents and DAS28 &lt;2.6 (i.e. remission). The proteins with the strongest evidence for association were analysed in an independent, replication dataset. Finally, subnetwork analysis was carried out using the Disease Module Detection algorithm and biological plausibility of identified proteins was assessed by enrichment analysis. Results: A total of 180 patients with RA were included in the discovery dataset and 58 in the validation dataset from a UK-based prospective multicentre study. Ten individual proteins were found to be significantly associated with RA clinical outcome measures. The association of T-complex protein 1 subunit g with DAS28 remission was replicated in an independent cohort. Subnetwork analysis of the 10 proteins from the regression analysis identified the ontological theme, with the strongest associations being with acute phase and acute inflammatory responses. Conclusion: This longitudinal study of 180 patients with RA commencing etanercept has identified several putative protein biomarkers of treatment response to this drug, one of which was replicated in an independent cohort

Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis

Objective: Biologic drug therapies represent a huge advance in the treatment of rheumatoid arthritis (RA). However, very good disease control is achieved in only 30% of patients, making identification of biomarkers of response a research priority. We undertook this study to test our hypothesis that differential DNA methylation patterns may provide biomarkers predictive of response to tumor necrosis factor inhibitor (TNFi) therapy in patients with RA. Methods: An epigenome-wide association study was performed on pretreatment whole blood DNA from patients with RA. Patients who displayed good response (n = 36) or no response (n = 36) to etanercept therapy at 3 months were selected. Differentially methylated positions were identified using linear regression. Variance of methylation at differentially methylated positions was assessed for correlation with cis-acting single-nucleotide polymorphisms (SNPs). A replication experiment for prioritized SNPs was performed in an independent cohort of 1,204 RA patients. Results: Five positions that were differentially methylated between responder groups were identified, with a false discovery rate of <5%. The top 2 differentially methylated positions mapped to exon 7 of the LRPAP1 gene on chromosome 4 (cg04857395, P = 1.39 × 10−8 and cg26401028, P = 1.69 × 10−8). The A allele of the SNP rs3468 was correlated with higher levels of methylation for both of the top 2 differentially methylated positions (P = 2.63 × 10−7 and P = 1.05 × 10−6, respectively). Furthermore, the A allele of rs3468 was correlated with European League Against Rheumatism nonresponse in the discovery cohort (P = 0.03; n = 56) and in the independent replication cohort (P = 0.003; n = 1,204). Conclusion: We identify DNA methylation as a potential biomarker of response to TNFi therapy, and we report the association between response and the LRPAP1 gene, which encodes a chaperone of low-density lipoprotein receptor–related protein 1. Additional replication experiments in independent sample collections are now needed

Population Pharmacokinetic Analysis and Simulation of Alternative Dosing Regimens for Biosimilars to Adalimumab and Etanercept in Patients with Rheumatoid Arthritis

\ua9 2024 by the authors.Efficacy to biologics in rheumatoid arthritis (RA) patients is variable and is likely influenced by each patient’s circulating drug levels. Using modelling and simulation, the aim of this study was to investigate whether adalimumab and etanercept biosimilar dosing intervals can be altered to achieve therapeutic drug levels at a faster/similar time compared to the recommended interval. RA patients starting subcutaneous Amgevita or Benepali (adalimumab and etanercept biosimilars, respectively) were recruited and underwent sparse serum sampling for drug concentrations. Drug levels were measured using commercially available kits. Pharmacokinetic data were analysed using a population approach (popPK) and potential covariates were investigated in models. Models were compared using goodness-of-fit criteria. Final models were selected and used to simulate alternative dosing intervals. Ten RA patients starting the adalimumab biosimilar and six patients starting the etanercept biosimilar were recruited. One-compartment PK models were used to describe the popPK models for both drugs; no significant covariates were found. Typical individual parameter estimates were used to simulate altered dosing intervals for both drugs. A simulation of dosing the etanercept biosimilar at a lower rate of every 10 days reached steady-state concentrations earlier than the usual dosing rate of every 7 days. Simulations of altered dosing intervals could form the basis for future personalised dosing studies, potentially saving costs whilst increasing efficacy

Differential DNA methylation correlates with response to methotrexate in rheumatoid arthritis

Objectives: Identifying blood-based biomarkers that predict treatment response in RA is a clinical priority. We investigated differential DNA methylation as a candidate biomarker of response for the first-line drug used in RA, MTX. Methods: DNA methylation was measured in DNA samples from individuals recruited to the Rheumatoid Arthritis Medication Study. Differentially methylated positions were compared between whole blood samples collected at baseline and at 4 weeks from patients who, by 6 months, had a good (n = 34) or poor response (n = 34) to MTX using linear modelling, adjusting for gender, age, cell composition, baseline 28-joint disease activity score (DAS28) and smoking status. Analyses also compared methylation with changes in DAS28 and changes in swollen joint count and tender joint count, and changes in CRP over the initial 6 months after MTX commencement. Differentially methylated positions showing significant differences with any response parameter were tested using pyrosequencing in an independent group of 100 patients from the Rheumatoid Arthritis Medication Study. Results: In the discovery group, two CpG sites showed methylation changes at 4 weeks associated with clinical EULAR response by 6 months. Significant changes in methylation for three differentially methylated positions associated with change in tender joint counts, three with change in swollen joint count and a further four with change in CRP. Of the 12 CpGs, four showed replicated association in an independent dataset of samples from the Rheumatoid Arthritis Medication Study. Conclusion: These data represent an advance on current practice by contributing to a personalized medicine strategy allowing an escalation or change in therapy as early as 4 weeks

Cardiovascular risk profile and management of atrial fibrillation in India: Real world data from RealiseAF survey

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia with high risk for many cardiovascular (CV) complications. Adherence to recommended management guidelines is important to avoid complications. In India, there is little knowledge on how AF is managed in real world. METHODS: This is a cross-sectional study of patients in India enrolled in RealiseAF survey between February 2010 and March 2010 with a diagnosis of AF within the last 12 months. RESULTS: From 15 centers, 301 patients {mean age 59.9 years (14.4); 52.5% males} were recruited. AF was controlled in 50% of patients with 77 (26.7%) in sinus rhythm and 67 (23.3%) with heart rate <80beats/min. Hypertension (50.8%), valvular heart disease (40.7%), heart failure (25.9%), and diabetes (20.4%) were the most common underlying CV diseases. Increased risk for stroke (CHADS2 score≥2) was present in 36.6%. Most of the patients (85%) were symptomatic. AF was paroxysmal, persistent, and permanent in 28.7%, 22.7%, and 34.3% respectively. In 14%, AF was diagnosed as first episode. Forty-six percent of patients had rate control, 35.2% rhythm control, 0.3% both strategies, and 18.4% received no therapy for AF before the visit. At the end of the visit, adoption to rate control strategy increased to 52.3% and patients with no therapy decreased to 7%. CONCLUSION: AF in India is not adequately controlled. Concomitant CV risk factors and risk of stroke are high. The study underscores the need for improved adoption of guideline-directed management for optimal control of AF and reducing the risk of stroke