Type 2 Diabetes Therapy Research Articles

Towards quadruple therapy for heart failure with reduced ejection fraction: DAPA-HF secondary analysis data

Patients with heart failure with reduced ejection fraction (HFrEF), despite optimal evidence-based treatment, have a high residual risk of adverse outcomes. The favorable results of studies on cardiovascular safety and the effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes (T2D), including outcomes associated with heart failure, were the reason for studying the effectiveness in patients with HFrEF regardless of the T2D status. For the first time in the DAPA-HF study, the SGLT2 inhibitor dapagliflozin in patients with HFrEF showed a positive effect on hard endpoints. Data of the secondary analysis confirmed the effectiveness of dapagliflozin regardless of the T2D status, therapy, age, and quality of life. The results of DAPA-HF have become a serious statement for changing the standards of the guideline-recommended therapy of HFrEF.

Feruloylated oligosaccharides and ferulic acid alter gut microbiome to alleviate diabetic syndrome

Gut microbiome has been proven to be involved in the development of type 2 diabetes (T2D). Additionally, increasing evidence showed that the composition of gut microbiome is highly associated with the outcome of T2D therapy. Previously we demonstrated that feruloylated oligosaccharides (FOs) and ferulic acid (FA) alleviated diabetic syndrome in rats, but the detailed mechanism has not been explored yet. In this study we strived to characterize how FOs and FA altered the gut microbiome and related metabolome in diabetic rats by using high-throughput sequencing of 16S rRNA and gas chromatography (GC). Our results showed that FOs reduced the abundance of Lactobacillus, Ruminococcus, Oscillibacter, and Desulfovibrio, but increased the abundance of Akkermansia, Phascolarctobacterium and Turicibacter. The structure of gut microbiome in FOs treated rats was similar with healthy rats rather than diabetic rats. Likewise, FA decreased the portion of Lactobacillus, Ruminococcus, but promoted the growth of Bacteroides, Blautia, Faecalibacterium, Parabacteroides and Phascolarctobacterium. Additionally, the short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs), the main bacterial lipid metabolites in gut mediating host glucose metabolism, was dramatically elevated along with FOs and FA treatment. Our findings indicated that FOs and FA attenuated diabetic syndrome in rats most likely by modulating the composition and metabolism of gut microbiome. The study gives new insight into the mechanism underlying the anti-diabetes effect of functional foods as well as facilitates the development of dietary supplements for diabetic patients.

2216-PUB: Patient Preferences for Newer Oral Therapies in Type 2 Diabetes

ADA/EASD guidelines emphasize the importance of patient engagement in therapy decisions. Beyond glycemic effects of type 2 diabetes (T2D) therapies, only SGLT2i and GLP-1RA have cardiovascular (CV) benefits. Key attributes of such therapies may influence their use/adoption. We evaluated patient preferences towards three oral T2D therapies using conjoint analysis. This analysis used an online survey, completed by 553 respondents with T2D in the U.S. (mean age ±SD was 64±9; 55% had CV risk; 27% had CV disease), to present 7 hypothetical, blinded pair-wise drug profile comparison choices composed of different benefit-risk attributes and effect ranges (levels). Attributes/levels were derived from combinations of phase 3 trial data for empagliflozin 25mg (SGLT2i), oral semaglutide 14mg (GLP-1RA) and sitagliptin 100mg (DPP-4i). The predicted therapy preference outcomes and the relative importance of one attribute relative to another were calculated (in %). The preference outcome was highest for the profile matching empagliflozin, ranked first by 56% (z-test, p<0.05), versus 38% for sitagliptin and 6% for oral semaglutide. Results were overall consistent in subgroup analyses. Genital infection risk was the most important perceived attribute with a relative score of 19% (z-test, p<0.05). Second and similarly important were fasting requirements (15%), weight reduction (15%), risk of vomiting (14%) and CV benefit (12%). Next was risk of nausea (11%). Last were HbA1c reduction (8%) and ability to take medication with other drugs (6%). While blinded to drug name/dose, respondents were also asked to choose explicitly between drug profiles similar to empagliflozin (chosen by 41%), sitagliptin (31%), oral semaglutide (11%), and ’none of the options’ (17%). The drug profile comparable to empagliflozin was the preferred agent; however, CV benefit was not the top patient priority. A shared physician-patient decision model and increased patient education are needed to ensure optimal use of guideline directed therapies in T2D. Disclosure G. Savarese: Advisory Panel; Self; AstraZeneca. Consultant; Self; Genesis, Societ Prodotti Antibiotici. Research Support; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Vifor Pharma Group. Speaker’s Bureau; Self; Roche Pharma, Servier, Vifor Pharma Group. A. Sharma: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Roche Pharma. Research Support; Self; Bristol-Myers Squibb, Merck & Co., Inc. Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation. C. Pang: None. R. Wood: Consultant; Self; Abbott, ADOCIA, American Diabetes Association, Ascensia Diabetes Care, Boehringer Ingelheim Pharmaceuticals, Inc., CeQur Corporation, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation. Employee; Self; dQ&A Market Research Inc. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. N. Soleymanlou: Employee; Self; Boehringer Ingelheim (Canada) Ltd. Funding Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance

633-P: Impact of Simulation-Based CME on Clinicians’ Knowledge and Competence Related to Hypoglycemia Management

We sought to determine if real-time patient simulation technology, designed to mimic a patient visit, could improve clinicians’ knowledge/competence regarding the management of hypoglycemia in patients with type 2 diabetes (T2D). The patient simulation technology, DecisionSim, was incorporated as part of a live symposium, and changes in competence and knowledge were evaluated using pre-/post-assessment questions. A Chi-Square test was used to analyze the percentage of correct responses and determine statistical significance (p <0.05 indicated statistical significance). The live activity took place on October 26, 2018. In total, 66 allied health professionals (PAs, RNs, NPs, PharmDs, CDE/RDs) and 41 MDs/DOs answered the assessment questions. An increase in knowledge was observed, albeit not statistically significant (4% relative increase compared to baseline, p = 0.6). A significant increase in competence in selecting the most appropriate treatment to address hypoglycemia risk for a patient with T2D was observed (120% relative increase compared to baseline, p <0.0001). 82% selected the correct treatment decisions in the branching simulation platform, including the intensification of therapy that addresses HbA1c goals while minimizing the risk of hypoglycemia in a virtual patient with T2D. Additionally, 83% indicated in the post-activity survey that they would make changes to practice based on information received, including to provide patient-centered care, assess the current diabetes guidelines, and use diabetes treatments that minimize hypoglycemia. Continued educational gaps were identified: lack of knowledge about the benefits of GLP-1RA/insulin combinations (17%), and lack of competence in individualizing T2D therapy in the context of hypoglycemia risk (21%). These results indicate that simulation-based CME can lead to significant improvements in competence related to hypoglycemia management, as well as commitment to change among learners. Disclosure S. Karandrea: None. N. Agarwal: None. A. Jamrogiewicz: None. Funding Sanofi US (IME-2017-12078)

Haplotypes of the Mutated SIRT2 Promoter Contributing to Transcription Factor Binding and Type 2 Diabetes Susceptibility.

Genetic variability is an important causative factor for susceptibility and pathogenesis of type 2 diabetes (T2D). Histone deacetylase, sirtuin 2 (SIRT2), plays regulatory roles in glucose metabolism and insulin sensitivity. However, whether the SIRT2 variants or haplotypes contribute to T2D risk remain to be elucidated. In this study, we first detected three novel polymorphisms (P-MU1, P-MU2, and P-MU3) in the promoter of SIRT2 in the Chinese population. All pairwise sets of the three loci were strongly in linkage disequilibrium. Next, we constructed the haplotype block structure, and found H1-GGC and H2-CCA accounted for the most (total 91.8%) in T2D. The haplotype combination H1-H1-GGGGCC displayed a high risk for T2D (OR = 2.03, 95% CI = 1.12–3.72). By association analysis, we found the individuals carrying H1-H1-GGGGCC had significantly higher fasting plasma glucose and glycated hemoglobin. The haplotype H1-GGC presented a 6.74-fold higher promoter activity than H2-CCA, which was consistent with the correlation results. Furthermore, we clarified the mechanism whereby the C allele of both the P-MU1 and P-MU2 loci disrupted the signal transducer and activator of transcription 1 (STAT1) binding sites, leading to the attenuation of the SIRT2 transcription. Together, these data suggest that the linked haplotype GGC could be considered as a promising marker for T2D diagnosis and therapy assessment.

Longitudinal association of type 2 diabetes and insulin therapy with muscle parameters in the KORA-Age study.

The aim of the current study was to investigate the association of type 2 diabetes (T2D) and insulin treatment with changes in muscle mass, muscle strength, and physical performance in older adults. In 731 participants of the population-based KORA-Age study aged 74.6 ± 6.2years (T2D: n = 118; insulin treatment: n = 20), skeletal muscle index (SMI [kg/m2]), hand grip strength (GS [kg]), and a timed up and go test (TUG [s]) were performed at baseline and after a follow-up time of 3years. The association of T2D and insulin therapy with changes in muscle parameters was analyzed using linear regression models. After adjustment for sex, age, BMI, physical activity, smoking, and multimorbidity, T2D was associated with the change in SMI during follow-up (β - 0.1 (95% CI - 0.3 to - 0.02) kg/m2; p = 0.02), but not with a change in GS (β - 0.9 (95% CI - 1.9 to 0.04) kg) or TUG (β - 0.1 (95% CI - 0.7 to 0.5) s). Insulin therapy was positively associated with change in SMI (β 0.6 (95% CI 0.3-0.9) kg/m2; p = 0.001), but not in GS (β - 1.6 (95% CI - 4.1 to 0.8) kg) or TUG (β 1.6 (95% CI - 0.2-3.4) s) in comparison with treatment with oral anti-diabetic medication alone. Participants with T2D showed an accelerated decline in muscle mass compared to non-diabetic participants. Insulin therapy was associated with preserved muscle mass, but not muscle function parameters, indicating a discrepancy between muscle mass and function in this high-risk population.

"H" for Heterogeneity in the Algorithm for Type 2 Diabetes Management.

Genetic, socioeconomic and clinical features vary considerably among individuals with type 2 diabetes (T2D) influencing disease development, progression and response to therapy. Although a patient-centred approach to pharmacologic therapy of T2D is widely recommended, patients are often treated similarly, irrespective of the differences that may affect therapeutic response. Addressing the heterogeneity of T2D is a major task of diabetes research to lower the high rate of treatment failure as well as to reduce the risk of long-term complications. A pathophysiology-based clustering system seems the most promising to help in the stratification of diabetes in terms of complication risk and response to treatment. This urges for clinical studies looking at novel biomarkers related to the different metabolic pathways of T2D and able to inform about the therapeutic cluster of each patient. Here, we review the main settings of diabetes heterogeneity, to what extent it has been already addressed and the current gaps in knowledge towards a personalized therapeutic approach that considers the distinctive features of each patient.

Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes.

Obesity has been described as a global epidemic and is a low-grade chronic inflammatory disease that arises as a consequence of energy imbalance. Obesity increases the risk of type 2 diabetes (T2D), by mechanisms that are not entirely clarified. Elevated circulating pro-inflammatory cytokines and free fatty acids (FFA) during obesity cause insulin resistance and ß-cell dysfunction, the two main features of T2D, which are both aggravated with the progressive development of hyperglycemia. The inflammatory kinase c-jun N-terminal kinase (JNK) responds to various cellular stress signals activated by cytokines, free fatty acids and hyperglycemia, and is a key mediator in the transition between obesity and T2D. Specifically, JNK mediates both insulin resistance and ß-cell dysfunction, and is therefore a potential target for T2D therapy.

Metabolites Linking the Gut Microbiome with Risk for Type 2 Diabetes.

An increasing body of evidence suggests that the gut microbiome influences the pathogenesis of insulin resistance and type 2 diabetes (T2D). In this review, we will discuss the latest findings regarding the mechanisms linking the gut microbiome and microbial metabolites with T2D and therapeutic approaches based on the gut microbiota for the prevention and treatment of T2D. Alterations in the gut microbial composition are associated with the risk of T2D. The gut microbiota can metabolize dietary- and host-derived factors to produce numerous microbial metabolites, which are involved in metabolic processes modulating nutrition and energy harvest, gut barrier function, systemic inflammation, and glucose metabolism. Microbial metabolites are important mediators of microbial-host crosstalk impacting host glucose metabolism. Furthermore, microbiome-based interventions may have beneficial effects on glycemic control. Future research is required to develop personalized T2D therapy based on microbial composition and/or metabolites.

Natural plant-derived polygalacturonic acid-oleanolic acid assemblies as oral-delivered nanomedicine for insulin resistance treatment

Exogenous insulin administration is still the most used treatment for diabetes (mainly used for type-1 diabetes in clinic), however type 2 diabetes (T2D) with the characteristics of insulin resistance accounts for the vast majority proportion (90–95%) of diabetic population, which makes insulin function failure. Currently, many efforts have been devoted to insulin delivery with nanomedicine means, whereas the treatment of insulin resistance in T2D using nanotechnology strategy is rarely reported. In this study, we transformed a plant-derived natural insulin sensitizer into biocompatible nano-transport system, where the natural insulin sensitizer oleanolic acid (OA) was conjugated onto natural polymer polygalacturonic acid (PGA) to form self-assembled micelles as oral administrated nanomedcine for insulin resistance treatment in T2D. In vitro and in vivo investigation demonstrated that OA loaded PGA-OA micelles possess stability to cross the gastrointestinal barriers and improve drug intestinal absorption, remarkably maintaining plasma drug concentration for a longer time. Therefore, this formulation manifested good reversal effect on insulin resistance in the T2D rat model, and thereby exhibited long-term outcomes in glucose level control even after drug withdrawal. Additionally, the molecular mechanism of OA loaded PGA-OA mediated insulin-resistant reversal was found that it was probable mediated by promoting IRS-1/PI3K/AKT signaling pathway and inhibiting the activity of PTP1B enzyme simultaneously. In this regard, such a facile, safe and potent nanomedicine strategy may be promising alternative for long-acting insulin-resistant treatment in T2D therapy.

Comprehensive Proteomics Analysis of Stressed Human Islets Identifies GDF15 as a Target for Type 1 Diabetes Intervention

Type 1 diabetes (T1D) results from the progressive loss of β cells, a process propagated by pro-inflammatory cytokine signaling that disrupts the balance between pro- and anti-apoptotic proteins. To identify proteins involved in this process, weperformed comprehensive proteomics of human pancreatic islets treated with interleukin-1β andinterferon-γ, leading to the identification of 11,324 proteins, of which 387 were significantly regulated by treatment. We then tested the function of growth/differentiation factor 15 (GDF15), whichwas repressed by the treatment. We found that GDF15 translation was blocked during inflammation, and it was depleted in islets from individuals with T1D. The addition of exogenous GDF15 inhibited interleukin-1β+interferon-γ-induced apoptosis of human islets. Administration of GDF15 reduced by 53% the incidence of diabetes in NOD mice. Our approach provides a unique resource for the identification of the human islet proteins regulated by cytokines and was effective in discovering a potential target for T1D therapy.

Патогенетические подходы к ведению пациентов с сахарным диабетом 2 типа. Новые потребности и новые возможности

Insulin resistance (IR) is one of the key mechanisms underlying the development and progression of type 2 diabetes (T2D). IR can be diagnosed in prediabetes and even in the lack of the existing disorders of carbohydrate metabolism. This paper highlights the properties of a drug that improves tissue sensitivity to insulin, pioglitazone. This medication provides good glycemic control and reduces the risk of cardiovascular events. In patients with prediabetes and IR, pioglitazone slows the progression of carbohydrate metabolism disorders to T2D and also provides cardioprotective effect. In T2D, this agent could be of great interest in terms of intensifying the therapy as a part of complex treatment, in particular, when combined with dipeptidylpeptidase-4 inhibitors or sodium-glucose cotransporter 2 inhibitors. Current priorities of the rational choice of antidiabetic therapy for T2D require personalized management, targeting pathogenic mechanisms, and the correction of risk factors and comorbidities. Considering this, multiple effects of pioglitazone can be of crucial importance when deciding on patient selection.KEYWORDS: diabetes, hyperglycemia, insulin resistance, insulin sensitivity, thiazolidinediones, glycemic control.FOR CITATION: Demidova T.Yu., Plakhotnyaya V.M., Gritskevich E.Yu. Pathogenic management strategies for type 2 diabetes. New requirements and new potentialities. Russian Medical Inquiry. 2020;4(6):347–351. DOI: 10.32364/2587-6821-2020-4-6-347-351.

Centrality Analysis of Protein-Protein Interaction Networks and Molecular Docking Prioritize Potential Drug-Targets in Type 1 Diabetes.

Type 1 diabetes (T1D) occurs as a consequence of an autoimmune attack against pancreatic β- cells. Due to a lack of a clear understanding of the T1D pathogenesis, the identification of effective therapies for T1D is the active area in the research. The study purpose was to prioritize potential drugs and targets in T1D via systems biology approach. Gene expression data of peripheral blood mononuclear cells (PBMCs) and pancreatic β-cells in T1D were analyzed and differential expressed genes were integrated with protein-protein interactions (PPI) data. Multiple topological centrality parameters of extracted query-query PPI (QQPPI) networks were calculated and the interaction of more central proteins with drugs was investigated. Molecular docking was performed to further predict the interactions between drugs and the binding sites of targets. Central proteins were identified by the analysis of PBMC (MYC, ERBB2, PSMA1, ABL1 and HSP90AA1) and pancreatic β-cells (HSP90AB1, ESR1, RELA, RAC1, NFKB1, NFKB2, IKBKE, ARRB2 and SRC) QQPPI networks. Thirteen drugs which targeted eight central proteins were identified by further analysis of drug-target interactions. Some drugs which investigated for diabetes treatment in the experimental models of T1D were prioritized by literature verification, including melatonin, resveratrol, lapatinib, geldanamycin, eugenol and fostaminib. Finally, according on molecular docking analysis, lapatinib-ERBB2 and eugenol-ESR1 exhibited highest and lowest binding energy, respectively. This study presented promising results for the prioritization of potential drug-targets which might facilitate T1D targeted therapy and its drug discovery process more effectively.

Development of an Error Model for a Factory-Calibrated Continuous Glucose Monitoring Sensor with 10-Day Lifetime.

Factory-calibrated continuous glucose monitoring (FC-CGM) sensors are new devices used in type 1 diabetes (T1D) therapy to measure the glucose concentration almost continuously for 10–14 days without requiring any in vivo calibration. Understanding and modelling CGM errors is important when designing new tools for T1D therapy. Available literature CGM error models are not suitable to describe the FC-CGM sensor error, since their domain of validity is limited to 12-h time windows, i.e., the time between two consecutive in vivo calibrations. The aim of this paper is to develop a model of the error of FC-CGM sensors. The dataset used contains 79 FC-CGM traces collected by the Dexcom G6 sensor. The model is designed to dissect the error into its three main components: effect of plasma-interstitium kinetics, calibration error, and random measurement noise. The main novelties are the model extension to cover the entire sensor lifetime and the use of a new single-step identification procedure. The final error model, which combines a first-order linear dynamic model to describe plasma-interstitium kinetics, a second-order polynomial model to describe calibration error, and an autoregressive model to describe measurement noise, proved to be suitable to describe FC-CGM sensor errors, in particular improving the estimation of the physiological time-delay.

Therapeutic administration of Tregitope-Human Albumin Fusion with Insulin Peptides to promote Antigen-Specific Adaptive Tolerance Induction

Type 1 Diabetes (T1D) is an autoimmune disease that is associated with effector T cell (Teff) destruction of insulin-producing pancreatic beta-islet cells. Among the therapies being evaluated for T1D is the restoration of regulatory T cell (Treg) activity, specifically directed toward down-modulation of beta-islet antigen-specific T effector cells. This is also known as antigen-specific adaptive tolerance induction for T1D (T1D ASATI). Tregitopes (T regulatory cell epitopes) are natural T cell epitopes derived from immunoglobulin G (IgG) that were identified in 2008 and have been evaluated in several autoimmune disease models. In the T1D ASATI studies presented here, Tregitope peptides were administered to non-obese diabetic (NOD) mice at the onset of diabetes within two clinically-relevant delivery systems (liposomes and in human serum albumin [HSA]-fusion products) in combination with preproinsulin (PPI) target antigen peptides. The combination of Tregitope-albumin fusions and PPI peptides reduced the incidence of severe diabetes and reversed mild diabetes, over 49 days of treatment and observation. Combining HSA-Tregitope fusions with PPI peptides is a promising ASATI approach for therapy of T1D.

Tolerogenic vaccine composited with islet-derived multipeptides and cyclosporin A induces pTreg and prevents Type 1 diabetes in murine model

ABSTRACTRegulatory T cells (Tregs) play a crucial role in the control of the initiation and progression of type 1 diabetes (T1D). Various immunological interventions including those to ex vivo expansion Tregs transfer, in vivo induction of peripherally derived Treg (pTreg) have been considered as promising approaches for T1D therapy. In this study, we developed a novel tolerogenic vaccine using four autoantigenic peptides of islet-derived with cyclosporine A (CsA) as the pTreg inducer, designated as GAD-IN+CsA. This vaccine immunized into prediabetic NOD mice subcutaneously could induce IL-10 and TGF-β expressing pTregs and lead to suppressing autoreactive T cells responses, resulting in the prevention of T1D in these animals. Furthermore, we demonstrated that CsA with autoantigenic peptides modulates dendritic cells (DCs) to become immature IL-10hiCD40lo DCs. Such modulated DCs could foster naïve CD4+CD25− T cell into Tregs when presenting antigen peptides in vitro. This novel approach offers an alternative strategy to induce pTregs to treat T1D.

Regulation of Hepatic Metabolism, Recent Advances, and Future Perspectives.

The purpose of this review is to provide a brief summary of recent advances in our understanding of liver metabolism. The critical role of the liver in controlling whole-body energy homeostasis makes such understanding crucial to efficiently design new treatments for metabolic syndrome diseases, including type 2 diabetes (T2D). Significant advances have been made regarding our understanding of the direct and indirect effects of insulin on hepatic metabolism and the communication between the liver and other tissues. Moreover, the catabolic functions of glucagon, as well as the importance of hepatic redox status for the regulation of glucose production, are emerging as potential targets to reduce hyperglycemia. A resolution to the long-standing question "insulin suppression of hepatic glucose production, direct or indirect effect?" is starting to emerge. New advances in our understanding of important fasting-induced hepatic metabolic fluxes may help design better therapies for T2D.

Sitagliptin favorably modulates immune-relevant pathways in human beta cells

Type 2 diabetes (T2D) is a condition characterized by hyperglycemia and chronic complications. Antidiabetic drugs and lifestyle interventions are the current gold standard therapy for T2D; current therapies, however, can only delay long-term diabetic complications and can additionally be associated with beta cell failure. While the mechanism of beta cell failure is well-studied, little is known about the immunological and inflammatory events associated with antidiabetic agents. Here we studied the effects of three antidiabetic drugs (Metformin, Sitagliptin, and Liraglutide) on immune-relevant pathways in a human beta cell line. Costimulatory molecule expression, cytokine secretion, and gene expression profiles were evaluated at different time points following challenge with the aforementioned antidiabetic agents. Our results showed that these three antidiabetic agents, particularly Sitagliptin, downregulate HLA Class I and II expression and upregulate the immune-regulatory molecules PD-L1 and CTLA4. Metformin and Liraglutide were shown to elicit significantly greater release of TNFa, IL-6, and GM-CSF, while Sitagliptin had a lesser effect on pro-inflammatory cytokine production. Gene expression analysis confirmed the aforementioned observations and also demonstrated upregulation of NOS2, SIRT1, SITR3, POLRMT, MRPL43 and NFkB with antidiabetic agents. We conclude that Sitagliptin most effectively modulates beneficial immune-relevant pathways in a human beta cell line.

Dapagliflozin: A Review in Type 2 Diabetes.

Dapagliflozin (Forxiga®) is a highly potent, reversible and selective sodium-glucose cotransporter-2 inhibitor indicated worldwide for the treatment of type 2 diabetes (T2D). In the EU, oral dapagliflozin once daily is approved for use as monotherapy (in patients who are intolerant of metformin) and as add-on combination therapy (with other glucose-lowering agents, including insulin) for T2D when diet and exercise alone do not provide adequate glycaemic control. In numerous well-designed clinical studies and their extensions, dapagliflozin as monotherapy and combination therapy with other antihyperglycaemic agents provided effective glycaemic control and reduced bodyweight and blood pressure (BP) across a broad spectrum of patients. Dapagliflozin reduced the rate of cardiovascular (CV) death or hospitalization for heart failure (HHF), did not adversely affect major adverse CV events (MACE) and possibly reduced progression of renal disease relative to placebo in patients with established atherosclerotic CV disease (CVD) or multiple risk factors for CVD. Dapagliflozin was generally well tolerated, with a low risk of hypoglycaemia; diabetic ketoacidosis (DKA), although rare, and genital infections were more common with dapagliflozin than placebo. Given its antihyperglycaemic, cardioprotective and possibly renoprotective properties and generally favourable tolerability profile, dapagliflozin provides an important option for the management of a broad patient population, regardless of the history of CVD.

Soluble Antigen Arrays Displaying Mimotopes Direct the Response of Diabetogenic T Cells.

Type 1 diabetes (T1D) is an autoimmune disorder which develops when insulin-producing, pancreatic beta cells are destroyed by an aberrant immune response. Current therapies for T1D either treat symptoms or cause global immunosuppression, which leave patients at risk of developing long-term complications or vulnerable to foreign pathogens. Antigen-specific immunotherapies have emerged as a selective approach for autoimmune diseases by inducing tolerance while mitigating global immunosuppression. We previously reported SAgAs with multiple copies of a multiple sclerosis (MS) autoantigen grafted onto hyaluronic acid (HA) as an efficacious therapy in experimental autoimmune encephalomyelitis. While the immune response of MS is distinct from that of T1D, the mechanism of SAgAs was hypothesized to be similar and via induction of immune tolerance to diabetes antigens. We synthesized SAgAs composed of HA polymer backbone conjugated with multiple copies of the T1D autoantigen mimotope p79 using aminooxy chemistry (SAgAp79) or using copper-catalyzed alkyne-azide cycloaddition (cSAgAp79) chemistry. SAgAs constructed using the hydrolyzable aminooxy linkage, thus capable of releasing p79, exhibited physicochemical properties similar to the triazole linkage. Both SAgAp79 versions showed high specificity and efficacy in stimulating epitope-specific T cells. SAgAs can be taken up by most immune cell populations but do not induce their maturation, and conventional dendritic cells are responsible for the brunt of antigen presentation within splenocytes. cSAgAp79 was more stimulatory than SAgAp79 both in vitro and in vivo, an effect that was ascribed to the peptide modification rather than the type of linkage. In summary, we provide here the first proof-of-principle that SAgA therapy could also be applicable to T1D.