Adherence and persistence rates of major antidiabetic medications: a review

The objective of this paper was to review the adherence and persistence rates of major antidiabetic medication classes (i.e., metformin, sulfonylureas, sodium glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, insulin, glucagon-like peptide-1 receptor agonists, and thiazolidinediones) by summarizing the major findings of the studies published since 2017. In addition, we reported the potential causes for low adherence and persistence of antidiabetic medications. Based on the literature, the highest rate of adherence and persistence was consistently observed in metformin users. Second to metformin were sodium glucose cotransporter-2 inhibitors. Injectable therapies such as insulin and glucagon-like peptide-1 receptor agonists trailed low on the adherence and persistence rates. To the best of our knowledge, no studies published since the year 2017 analyzed the adherence and persistence of thiazolidinediones independently. The most frequently cited cause for low adherence and persistence was the severity of adverse events. Baseline characteristics (e.g., baseline HbA1c level), demographic information (e.g., age, gender, or ethnicity), and comorbidity profiles also had significant impacts on adherence and persistence in patients with type 2 diabetes mellitus.

Computational Modelling of Glucose Uptake in the Enterocyte

We describe an implemented model of glucose absorption in the enterocyte, as previously published by Afshar et al. (2019), The model used mechanistic descriptions of all the responsible transporters and was built in the CellML framework. It was validated against published experimental data and implemented in a modular structure which allows each individual transporter to be edited independently from the other transport protein models. The composite model was then used to study the role of the sodium-glucose cotransporter (SGLT1) and the glucose transporter type 2 (GLUT2), along with the requirement for the existence of the apical Glut2 transporter, especially in the presence of high luminal glucose loads, in order to enhance the absorption. Here we demonstrate the reproduction of the figures in the original paper by using the associated model. EDITOR'S NOTE (v3): Instructions within the manuscript changed, in order to properly execute the model files. Spelling of author's name corrected in filenames. (v4): Abstract fixes.

Computational Modelling of Glucose Uptake in the Enterocyte

We describe an implemented model of glucose absorption in the enterocyte, as previously published by Afshar et al. Afshar et al. (2019), The model used mechanistic descriptions of all the responsible transporters and was built in the CellML framework. It was validated against published experimental data and implemented in a modular structure which allows each individual transporter to be edited independently from the other transport protein models. The composite model was then used to study the role of the sodium-glucose cotransporter (SGLT1) and the glucose transporter type 2 (GLUT2), along with the requirement for the existence of the apical Glut2 transporter, especially in the presence of high luminal glucose loads, in order to enhance the absorption. Here we demonstrate the reproduction of the figures in the original paper by using the associated model. EDITOR'S NOTE (v2): Instructions within the manuscript changed, in order to properly execute the model files. Spelling of author's name corrected in filenames.

Finerenone: A Novel Mineralocorticoid Receptor Antagonist for Cardiorenal Protection in CKD and T2DM

Objective: To describe the pharmacology, clinical and safety evidence, and relevance to clinical practice of finerenone. Data Sources: A literature search was conducted utilizing PubMed, MEDLINE, and clinicaltrials.gov with search terms of “finerenone” and “BAY94-8862.” Study Selection and Data Extraction All available studies with human participants in English were considered. Studies were included if they investigated drug pharmacology, efficacy, and safety information. Data Synthesis In addition to standard of care with a renin-angiotensin system inhibitor (RASi), finerenone lowered the risk of kidney disease progression (17.8% vs 21.1%) in patients with type 2 diabetes mellitus and chronic kidney disease compared to placebo. Similarly, finerenone reduced cardiovascular risk in patients with type 2 diabetes mellitus and chronic kidney disease compared to placebo (12.4% vs 14.2%). Relevance to Patient Care and Clinical Practice It is anticipated that finerenone will be added to therapy after a RASi and a sodium-glucose cotransporter-2 inhibitor, as tolerated, based on adverse events and potassium levels. Conclusions Finerenone offers a unique approach to further delay the progression of chronic kidney disease in patients with type 2 diabetes mellitus. It also provides another option for patients who cannot tolerate RASi or sodium-glucose cotransporter-2 inhibitors.

Effects of treatment with SGLT-2 inhibitors on arginine-related cardiovascular and renal biomarkers

Background In patients with type 2 diabetes (T2D) sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve glycaemic control as well as cardiovascular and renal outcomes. Their effects on l-arginine (Arg) related risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA) and the protective biomarker L-homoarginine (hArg) linking T2D to cardiovascular and renal disease have not yet been reported. Methods Plasma and 24-h urine samples taken before and after 6 weeks of treatment were available from two prospective, randomized, double-blind, placebo-controlled, cross-over trials with empagliflozin (71 patients analyzed, NCT02471963) and dapagliflozin (59 patients analyzed, NCT02383238). In these samples, concentrations of hArg, Arg, ADMA, SDMA, and creatinine were determined by liquid-chromatography coupled to tandem mass-spectrometry. Additionally, intraindividual changes of the biomarkers in plasma were correlated with intraindividual changes of clinical parameters. Results Treatment with empagliflozin and dapagliflozin was associated with a reduction of plasma hArg by 17.5% and 13.7% (both p < 0.001), respectively, and increase in plasma SDMA concentration of 6.7% and 3.6%, respectively (p < 0.001 and p < 0.05), while plasma Arg and ADMA concentrations were not significantly altered. 24-h urinary excretion of ADMA was reduced by 15.2% after treatment with empagliflozin (p < 0.001) but not after dapagliflozin treatment, while excretion of the other markers was not significantly altered. Renal clearance of SDMA was reduced by 9.1% and 3.9% for both drugs (both p < 0.05). A reduction in ADMA clearance was observable after empagliflozin treatment only (− 15.5%, p < 0.001), but not after dapagliflozin. Renal clearance of hArg and Arg was not significantly altered. Treatment effects on l-arginine related biomarkers were not constantly correlated with effects on glycated hemoglobin, fasting plasma glucose, body mass index, and systolic blood pressure. Conclusions Treatment with SGLT-2 inhibitors has divergent effects on Arg-related biomarkers and could affect risk estimates associated with these markers. The observed effects are unlikely to explain the known cardiovascular and renal benefits of treatment with empagliflozin or dapagliflozin but still may indicate new therapeutic approaches in patients treated with SGLT-2 inhibitors. Trial registrationhttp://www.clinicaltrials.gov: NCT02471963 (registered 15th June 2015, retrospectively registered) and NCT02383238.

Canagliflozin: from glycemic control to improvement of cardiovascular and renal prognosis in patients with type 2 diabetes mellitus. Resolution of Advisory Board

Inhibitors of the sodium-glucose cotransporter type 2 (SGLT2i) are a modern class of antihyperglycemic drugs with an insulin-independent mechanism of action. Due to its ability to effectively lower blood glucose levels, improve a number of other cardiometabolic parameters (body weight, blood pressure, uric acid), as well as reduce cardiovascular and renal risks, SGLT2i have become drugs of choice for many of patients with type 2 diabetes mellitus (T2DM). Meanwhile, along with the generally recognized classes-effects of this group of drugs, there are intragroup features, including those associated with their different selectivity in sodium-glucose cotransporters of types 1 and 2 (SGLT1 and SGLT 2). For example, one of the most studied SGLT2i, canagliflozin, in addition to its inhibitory activity against SGLT2, can also moderately block SGLT1 in the intestine and kidneys that could give a maximum efficiency in the control glycemia and others cardiometabolic parameters. In addition, canagliflozin improves not only cardiovascular, but also renal prognosis in patients with T2DM, which is reflected in the corresponding indications in the summary of product characteristics of the drug. This document summarize the established and new data regarding the efficacy and safety of canagliflozin, as well as its place in the treatment of T2DM.