The significance of metabolic alkalosis on acute decompensated heart failure: the ALCALOTIC study.

AIMS: To determine the prevalence and the impact on prognosis of metabolic alkalosis (MA) in patients admitted for acute heart failure (AHF). METHODS AND RESULTS: The ALCALOTIC is a multicenter, observational cohort study that prospectively included patients admitted for AHF. Patients were classified into four groups according to their acid-base status on admission: acidosis, MA, respiratory alkalosis, and normal pH (reference group for comparison). Primary endpoint was all-cause in-hospital mortality, and secondary endpoints included 30/90-day all-cause mortality, all-cause readmission, and readmission for HF. Associations between endpoints and acid-base alterations were estimated in a multivariate Cox regression model including sex, age, comorbidities, and Barthel index and expressed as hazard ratio (HR) with 95% confidence interval (95% CI). Six hundred sixty-five patients were included (84 years and 57% women), and 40% had acid-base alterations on admission: 188 (28%) acidosis and 78 (12%) alkalosis. The prevalence (95% CI) of MA was 9% (6.8-11.2%). Patients with MA were more women; had fewer comorbidities, better renal function, and higher left ventricle ejection fraction values; and received more treatment with oral acetazolamide during hospitalization and at discharge. MA was not associated with a higher risk of in-hospital mortality and 30/90-day all-cause mortality or readmissions but was associated with a significant increase in readmissions for HF at 30 and 90 days (adjusted HR [95% CI] 3.294 [1.397-7.767], p = 0.006 and 2.314 [1.075-4.978], p = 0.032). CONCLUSION: The prevalence of MA in patients admitted for AHF was 9%, and its presence was associated with more readmissions for HF but not with all-cause mortality.

Diagnosis of heart failure with preserved ejection fraction: a systematic narrative review of the evidence.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a common condition in clinical practice, affecting more than half of patients with HF. HFpEF is associated with morbidity and mortality and with considerable healthcare resource utilization and costs. Therefore, early diagnosis is crucial to facilitate prompt management, particularly initiation of sodium-glucose co-transporter 2 inhibitors. Although European guidelines define HFpEF as the presence of symptoms with or without signs of HF, left ventricular EF ≥ 50%, and objective evidence of cardiac structural and/or functional abnormalities, together with elevated natriuretic peptide levels, the diagnosis of HFpEF remains challenging. First, there is no clear consensus on how HFpEF should be defined. Furthermore, diagnostic tools, such as natriuretic peptide levels and resting echocardiogram findings, are significantly limited in the diagnosis of HFpEF. As a result, some patients are overdiagnosed (i.e., elderly people with comorbidities that mimic HF), although in other cases, HFpEF is overlooked. In this manuscript, we perform a systematic narrative review of the diagnostic approach to patients with HFpEF. We also propose a comprehensible algorithm that can be easily applied in daily clinical practice and could prove useful for confirming or ruling out a diagnosis of HFpEF.

Accelerated Carbonation of Vibro-Compacted Porous Concrete for Eco-Friendly Precast Elements.

This research studied the effect of accelerated carbonation in the physical, mechanical and chemical properties of a non-structural vibro-compacted porous concrete made with natural aggregates and two types of recycled aggregates from construction and demolition waste (CDW). Natural aggregates were replaced by recycled aggregates using a volumetric substitution method and the CO2 capture capacity was also calculated. Two hardening environments were used: a carbonation chamber with 5% CO2 and a normal climatic chamber with atmospheric CO2 concentration. The effect of curing times of 1, 3, 7, 14 and 28 days on concrete properties was also analysed. The accelerated carbonation increased the dry bulk density, decreased the accessible porosity water, improved the compressive strength and decreased the setting time to reach a higher mechanical strength. The maximum CO2 capture ratio was achieved with the use of recycled concrete aggregate (52.52 kg/t). Accelerate carbonation conditions led to an increase in carbon capture of 525% compared to curing under atmospheric conditions. Accelerated carbonation of cement-based products containing recycled aggregates from construction and demolition waste is a promising technology for CO2 capture and utilisation and a way to mitigate the effects of climate change, as well as promote the new circular economy paradigm.

Carbon Emission Evaluation of CO2 Curing in Vibro-Compacted Precast Concrete Made with Recycled Aggregates.

The objective of the present study was to explore three types of vibro-compacted precast concrete mixtures replacing fine and coarse gravel with a recycled/mixed concrete aggregate (RCA or MCA). The portlandite phase found in RCA and MCA by XRD is a "potential" CO2 sink. CO2 curing improved the compressive strength in all the mixtures studied. One tonne of the mixtures studied could be decarbonised after only 7 days of curing 13,604, 36,077 and 24,635 m3 of air using natural aggregates, RCA or MCA, respectively. The compressive strength obtained, XRD, TGA/DTA and carbon emission evaluation showed that curing longer than 7 days in CO2 was pointless. The total CO2 emissions by a mixture using CO2 curing at 7 days were 221.26, 204.38 and 210.05 kg CO2 eq/m3 air using natural aggregates, RCA or MCA, respectively. The findings of this study provide a valuable contribution to carbon emission evaluation of CO2 curing in vibro-compacted precast concrete with recycled/mixed concrete aggregates (RCA or MCA). The technology proposed in this research facilitates carbon capture and use and guarantees enhanced compressive strength of the concrete samples.

The Effect of Acanthocardia tuberculata Shell Powder as Filler on the Performance of Self-Compacting Mortar.

In this research, the feasibility of using Acanthocardia tuberculata shell waste from the canning industry in the manufacturing of self-compacting mortar (SCM) was tested. The seashells were finely ground to be used as filler instead of the limestone filler normally used in this type of SCM. First, a physicochemical and microstructural characterisation of all raw materials was carried out, including the particle size distribution of both fillers. Subsequently, the self-compactability properties in the fresh state of SCM were evaluated using a total substitution by volume of limestone filler for seashell powder, using different self-compactiblity parameters. The mineralogical phases of all the SCM tested were identified once hardened by means of X-ray diffraction technique, thermogravimetric and differential thermal analysis. In addition, the mechanical properties, water absorption capacity, dry bulk density and accessible porosity of water of hardened mortars at 28 days of curing were analysed. The effect of replacing limestone filler by Acanthocardia tuberculata filler resulted in a decrease in compressive strength of 29.43, 16.84 and 2.29%, respectively. The results indicate that it is possible to completely replace natural limestone filler with Acanthocardia tuberculata shell filler without significantly affecting the mechanical properties of SCM.

Effect of semaglutide on fatty liver disease biomarkers in patients with diabetes and obesity.

AIM: This work aims to assess the effect of weekly subcutaneous semaglutide on biomarkers of metabolic-associated fatty liver disease (MAFLD), namely the hepatic steatosis index (HSI) and the fibrosis-4 (FIB-4) index, at 24 weeks in outpatients attended to in internal medicine departments. METHODS: This study analyzed patients in an ongoing, multicenter, prospective, pre-post, uncontrolled cohort registry that enrolls unique, consecutive patients with type 2 diabetes treated with weekly subcutaneous semaglutide. Steatosis/fibrosis were determined by HSI (<30 ruled out, >36 steatosis) and FIB-4 (<1.3 ruled out, >2.67 fibrosis), respectively. RESULTS: The sample included 213 patients (46.9% women) with a median age of 64 (19) years. The median baseline body mass index and weight were 36.1 (8.4) kg/m2 and 98 (26.9) kg, respectively. A total of 99.9% had HSI values indicating steatosis, with a mean HSI of 47.9 (8.2). Additionally, 10.8% had fibrosis (FIB-4 > 2.67) and 42.72% had values in intermediate ranges (FIB-4 1.3-2.67). At 24 weeks, there was a significant reduction in HSI (-2.36 (95%CI 1.83-2.9) p < 0.00001) and FIB-4 (-0.075 (95%CI 0.015-0.14) p < 0.016), mainly related to declines in body weight, triglyceride levels, insulin resistance (estimated by the triglyceride-glucose index), and liver enzymes. CONCLUSION: These results show that weekly subcutaneous semaglutide had a beneficial effect on liver steatosis that went beyond glucose control. Its effects were mainly related to weight loss, a decline in biomarkers, and improvements in insulin sensitivity. For many patients, early detection is essential for improving MAFLD outcomes and may allow for selecting the most efficient treatment options.

Effectiveness of sacubitril-varsartan versus angiotensin converting enzyme inhibitors in patients hospitalized for acute heart failure: a retrospective cohort study of the RICA registry.

BACKGROUND: Sacubitril-valsartan has been shown to reduce hospitalizations and mortality in patients with heart failure (HF) and reduced ejection fraction. The PIONEER-HF trial demonstrated that initiation of the drug during acute HF hospitalization reduced NT-proBNP levels and a post-hoc analysis of the trial found a reduction in HF hospitalizations and deaths. Real-life studies in the elderly population are scarce. The aim of our study was to assess the effectiveness of sacubitril-valsartan versus angiotensin converting enzyme inhibitors (ACEI) in elderly patients who initiate this treatment during hospitalization for acute HF. METHODS: We conducted a retrospective cohort study using the Spanish acute heart failure registry (RICA) comparing rehospitalizations and deaths at 3 months and 1 year among patients aged 70 years or older who had initiated treatment with sacubitril-valsartan during hospitalization for acute HF versus those treated with ACEI. RESULTS: One hundred and ninety-nine patients hospitalized between October 2016 and November 2020 were included, with a median age of 82 years and high rate of comorbidity. Of these, 107 were treated with sacubitril-valsartan and 92 with ACEI. The adjusted OR for readmission for HF at 3 months was 0.906 (95% CI: 0.241-3.404) and for the combined variable readmission for HF or death at 3 months was 0.696 (95% CI: 0.224-2.167). The adjusted OR for HF readmission at one year was 0.696 (95% CI: 0.224 -2.167). and for the combined variable HF readmission or death at one year 0.724 (95% CI: 0.325-1.612). CONCLUSION: Treatment with sacubitril-valsartan initiated early in hospitalization for HF in elderly patients with high comorbidity was associated with a trend towards a reduction in readmissions and death due to HF compared to treatment with ACEI, which did not reach statistical significance either at 3 months or 1 year of follow-up.

Ternary Blends for Self-Compacting Mortars Production Composed by Electric Arc Furnace Dust and Other Industrial by-Products.

This study is framed within the circular economy model through the valorisation of industrial by-products. This research shows the results of producing self-compacting mortars (SCMs) with electric arc furnace dust (EAFD) and other industrial by-products such as fly ash, conforming (FA) or not conforming (NcFA), from coal-fired power plants, or recovery filler (RF) from hot-mix asphalt plants. Three batches of SCMs, each with one industrial-by product (FA, NcFA, or RF), and three levels of EAFD ratio incorporation (0%, 10%, 20%), were tested. An extra batch with a greater amount of FA was manufactured. When the incorporation ratio of EAFD rose, the mechanical strength decreased, due to the presence of a calcium zinc hydroxide dihydrate phase; nevertheless, this decrease diminished over time. All SCM mixes, except the 40C 40FA 20 EAFD mix, were above 20 MPa at 28 days. All mixes named 70C and 40C reached 40 and 30 MPa, respectively, at 90 days. Mixes with EAFD showed less capillarity and no difference in water absorption by immersion with respect to mixes without EAFD after 91 days. The SCMs designed proved to be stable in terms of leaching of the heavy metals contained in EAFD, where all the hardened SCMs were classified as inert.

Use of Carbonated Water as Kneading in Mortars Made with Recycled Aggregates.

The increased concern about climate change is revolutionising the building materials sector, making sustainability and environmental friendliness increasingly important. This study evaluates the feasibility of incorporating recycled masonry aggregate (construction and demolition waste) in porous cement-based materials using carbonated water in mixing followed (or not) by curing in a CO2 atmosphere. The use of carbonated water can be very revolutionary in cement-based materials, as it allows hydration and carbonation to occur simultaneously. Calcite and portlandite in the recycled masonry aggregate and act as a buffer for the low-pH carbonated water. Carbonated water produced better mechanical properties and increased accessible water porosity and dry bulk density. The same behaviour was observed with natural aggregates. Carbonated water results in an interlaced shape of carbonate ettringite (needles) and fills the microcracks in the recycled masonry aggregate. Curing in CO2 together with the use of carbonated water (concomitantly) is not beneficial. This study provides innovative solutions for a circular economy in the construction sector using carbonated water in mixing (adsorbing CO2), which is very revolutionary as it allows carbonation to be applied to in-situ products.

Performance of Sustainable Mortars Made with Filler from Different Construction By-Products.

One way to contribute to sustainability in the construction sector is through the incorporation of construction by-products from their own activities. This work intends to extend the possibilities for enhancement of these by-products through the incorporation of four different ones, as fillers, in mortar production. The influence of these incorporations in mortar production was compared with a reference mortar with siliceous filler in its fresh state; workability, entrained air content and fresh density, and in its hardened state; capillary water absorption, water vapour permeability and shrinkage (up to 91 days); and adhesive, compressive, and flexural strength; the last two were studied over time (up to 180 days). Despite the reduction in compressive strength, both in the short and long term, there was a gain in adhesive strength when the construction by-products were incorporated. Regarding the physical properties and durability studied, no relevant differences were found with respect to the reference mortar. According to the European Specifications, these mortars could be used as regular or coloured rendering and plastering mortars, and masonry mortars, and these findings promote the circular economy in the construction sector.

The Performance of Concrete Made with Secondary Products-Recycled Coarse Aggregates, Recycled Cement Mortar, and Fly Ash-Slag Mix.

The properties of cement concrete using waste materials-namely, recycled cement mortar, fly ash-slag, and recycled concrete aggregate-are presented. A treatment process for waste materials is proposed. Two research experiments were conducted. In the first, concretes were made with fly ash-slag mix (FAS) and recycled cement mortar (RCM) as additions. The most favorable content of the concrete additive in the form of RCM and FAS was determined experimentally, and their influence on the physical and mechanical properties of concrete was established. For this purpose, 10 test series were carried out according to the experimental plan. In the second study, concretes containing FAS-RCM and recycled concrete aggregate (RCA) as a 30% replacement of natural aggregate (NA) were prepared. The compressive strength, frost resistance, water absorption, volume density, thermal conductivity, and microstructure were researched. The test results show that the addition of FAS-RCM and RCA can produce composites with better physical and mechanical properties compared with concrete made only of natural raw materials and cement. The detailed results show that FAS-RCM can be a valuable substitute for cement and RCA as a replacement for natural aggregates. Compared with traditional cement concretes, concretes made of FAS, RCM, and RCA are characterized by a higher compressive strength: 7% higher in the case of 30% replacement of NA by RCA with the additional use of the innovative FAS-RCM additive as 30% of the cement mass.

Hospitalización: el momento más vulnerable / Hospitalization: the most vulnerable time

La hospitalización por IC forma parte de la historia natural de la enfermedad e identifica un agravamiento, incluso en la primera hospitalización, con mayor riesgo de muerte y nuevas rehospitalizaciones tras el alta. Para abordar esta vulnerabilidad, resulta fundamental actuar sobre la transición del paciente antes y después del alta, integrando medidas organizativas y la mejora del tratamiento capaz de modificar la enfermedad. Los estudios PIONEER y TRANSITION han demostrado que el sacubitrilo-valsartán puede iniciarse durante la hospitalización, se tolera y es seguro, y su administración precoz mejora marcadores pronósticos y reduce el riesgo de rehospitalización respecto a enalapril. Este beneficio se extiende a pacientes con IC de novo y sin tratamiento previo a los inhibidores de la enzima de conversión de la angiotensina. Por lo tanto, se dispone de nuevas oportunidades en el tratamiento de estos pacientes, cuya implementación es necesaria para reducir la vulnerabilidad asociada con la hospitalización y frenar la progresión de la enfermedad. Información sobre el suplemento: este artículo forma parte del suplemento titulado «Controversias para una nueva era en el tratamiento de la insuficiencia cardiaca», que ha sido patrocinado por Novartis

Hospitalization for heart failure is part of the natural history of the disease and indicates a deterioration. Even the first hospitalization is associated with an increased risk of death and of repeat hospitalization after discharge. During this period of vulnerability, it is essential that transitional care is carefully managed both before and after discharge: organizational measures should be coordinated and treatment that can modify the disease course should be boosted. The PIONEER and TRANSITION studies demonstrated that sacubitril-valsartan can be started during hospitalization, that it is well tolerated and safe, and that its early administration improves prognostic markers and reduces the risk of rehospitalization compared with enalapril. These benefits extend to patients with de novo heart failure and to those who have not previously received angiotensin-converting enzyme inhibitors. Consequently, there are new opportunities for providing these patients with the treatment needed to reduce the risks associated with hospitalization and to slow disease progression. Supplement information: this article is part of a supplement entitled "Questions on a new era for heart failure treatment" which is sponsored by Novartis

Optimum Particle Size of Treated Calcites for CO2 Capture in a Power Plant.

This work has analyzed the influence of the particle size of a calcite from a quarry, whether original, calcined, or rehydrated, on the efficiency of CO2 capture of the gases emitted in a coal-fired power plant. Three different particle sizes 0.5 mm, 0.1 mm, and 0.045 mm have been studied. The calcination had a minimal effect on the particle size of the smaller samples A1045 and A1M1 (<30 µm). The N2 isotherms and the CO2 adsorption isotherms at 0 °C showed a very significant increase in the surface of the calcined and rehydrated samples (A15CH, A1045CH, and A1M1CH) with respect to the calcined or original samples. The results obtained showed that the capture of CO2 for the sample A1M1, with a smaller average particle size (<30 µm, is the most effective. For the sample A1M1 calcined and completely rehydrated (Ca(OH)2), the chemical adsorption of CO2 to form CaCO3 is practically total, under the experimental conditions used (550 °C and CO2 flow of 20 mL min-1). The weight increase was 34.11% and the adsorption capacity was 577.00 mg g-1. The experiment was repeated 10 times with the same sample A1M1 calcined and rehydrated. No appreciable loss of adsorption capacity was observed.

A Double Barrier Technique with Hydrotalcites for Pb Immobilisation from Electric Arc Furnace Dust.

A new line of mortars incorporating hydrotalcites was developed. This research article shows the results of a study of a double barrier technique (DBT) for Pb immobilisation from electric arc furnace dust (EAFD) in mortars with the addition of three different hydrotalcites (H1, H2, and H3). Electric arc furnace dust (EAFD) is a hazardous waste due to its heavy metal leachability. The aim was to obtain a mortar in which, due to its chemical composition, heavy metal leaching satisfied environmental criteria. Previously, a physical and chemical characterisation of mortar material components was carried out. The leaching behaviour of Pb from EAFD in double barrier (DB) mortars with different hydrotalcites was analysed for compressive strength to determine treatment effectiveness. DB mortars could be considered monoliths because their compressive strengths were higher than 1 MPa but exhibited a decrease due to hydrotalcite incorporation. The mortar EAFD25_H2 (with ethylenediaminetetraacetate (EDTA) in the interlayer of the hydrotalcite) showed one minor reduction in compressive strength with respect to the reference mortar because formation of Portlandite was observed, which is a characteristic of cement hydration. The conventional immobilisation mortar (EAFD25) did not achieve Pb immobilisation. However, DB mortars with dimercaptosuccinate (DMSA) in the interlayer of the hydrotalcite reduced Pb release by ~50%, from 20.29 mg kg-1 (EAFD25) to 9.88 mg kg-1 (EAFD25_H3). In addition, EAFD25_H3 included the lowest hydrotalcite content, thereby improving the immobilisation ratio. The results of this study contribute to better Pb immobilisation, thus satisfying environmental criteria.

Análisis de coste-efectividad de dapagliflozina en comparación con los inhibidores de la DPP4 y otros antidiabéticos orales en el tratamiento de la diabetes mellitus tipo 2 en España / Cost-effectiveness analysis of dapagliflozin compared to DPP4 inhibitors and other oral antidiabetic drugs in the treatment of type-2 diabetes mellitus in Spain

OBJETIVO: Evaluar la eficiencia de la terapia combinada de metformina y dapagliflozina, un nuevo antidiabético oral con un mecanismo de acción independiente de la insulina, en el tratamiento de la diabetes mellitus tipo 2 (DM2) en comparación con inhibidores de DPP4, sulfonilureas y tiazolidindionas, combinados también con metformina. DISEÑO: Análisis de coste-efectividad utilizando un modelo de simulación de eventos discretos a partir de los resultados de los ensayos clínicos disponibles y considerando un horizonte temporal de toda la vida del paciente. Emplazamiento: Perspectiva del Sistema Nacional de Salud. PARTICIPANTES: El modelo simuló la historia natural de 30.000 pacientes con DM2 para cada opción comparada. MEDICIONES PRINCIPALES: Años de vida ajustados por calidad (AVAC) y consecuencias económicas del manejo de la enfermedad y sus complicaciones. Se consideraron los costes directos (actualizados a euros de 2013) y se aplicó un descuento del 3% tanto para costes como para resultados en salud. RESULTADOS: El análisis principal comparó dapagliflozina con los inhibidores de DPP4, resultando dapagliflozina como una opción de tratamiento que aportaría una ligera mayor efectividad (0,019 AVAC) con menores costes totales asociados (−42 Euros). En los análisis adicionales, dapagliflozina fue una opción coste-efectiva en comparación con sulfonilureas y tiazolidindionas con razones de coste por AVAC ganado de 3.560 Euros y 2.007 Euros, respectivamente. Los análisis de sensibilidad univariantes y probabilístico confirmaron la solidez de los RESULTADOS: CONCLUSIONES: Los resultados del análisis realizado sugieren que dapagliflozina, en combinación con metformina, sería una alternativa coste-efectiva en el contexto español para el tratamiento de la DM2

OBJECTIVE: To assess the efficiency of the combined therapy with metformin and dapagliflozin, a new oral anti-diabetic drug with an insulin-independent mechanism of action, in the treatment of type-2 diabetes mellitus (T2DM) compared to DPP4 inhibitors, sulphonylureas and thiazolidindiones, also combined with metformin. DESIGN: Cost-effectiveness analysis using a discrete event simulation model based on the results of the available clinical trials and considering patient's entire life as time horizon. SETTING: National Health System perspective. PARTICIPANTS: The model simulated the natural history of 30,000 patients with T2DM for each of the options compared. MAIN MEASUREMENTS: Quality-adjusted life-years (QALY) and economic consequences of managing the disease and its complications. The analysis considered direct costs updated to 2013. A discount rate of 3% was applied to costs and health outcomes. RESULTS: In the main analysis comparing dapagliflozin with DPP4 inhibitors, dapagliflozin resulted in a treatment option that would provide a slightly higher effectiveness (0.019 QALY) and lower overall associated costs (- 42 Euros). In the additional analyses, dapagliflozin was a cost-effective option compared with sulphonylureas and thiazolidinediones resulting in a cost per QALY gained of 3,560 Euros and 2,007 Euros, respectively. The univariate and probabilistic sensitivity analyses confirmed the robustness of the RESULTS: CONCLUSIONS: The results of the analyses performed suggested that dapagliflozin, in combination with metformin, would be a cost-effective alternative in the Spanish context for the treatment of T2DM

[Cost-effectiveness analysis of dapagliflozin compared to DPP4 inhibitors and other oral antidiabetic drugs in the treatment of type-2 diabetes mellitus in Spain]. / Análisis de coste-efectividad de dapagliflozina en comparación con los inhibidores de la DPP4 y otros antidiabéticos orales en el tratamiento de la diabetes mellitus tipo 2 en España.

OBJECTIVE: To assess the efficiency of the combined therapy with metformin and dapagliflozin, a new oral anti-diabetic drug with an insulin-independent mechanism of action, in the treatment of type-2 diabetes mellitus (T2DM) compared to DPP4 inhibitors, sulphonylureas and thiazolidindiones, also combined with metformin. DESIGN: Cost-effectiveness analysis using a discrete event simulation model based on the results of the available clinical trials and considering patient's entire life as time horizon. SETTING: National Health System perspective. PARTICIPANTS: The model simulated the natural history of 30,000 patients with T2DM for each of the options compared. MAIN MEASUREMENTS: Quality-adjusted life-years (QALY) and economic consequences of managing the disease and its complications. The analysis considered direct costs updated to 2013. A discount rate of 3% was applied to costs and health outcomes. RESULTS: In the main analysis comparing dapagliflozin with DPP4 inhibitors, dapagliflozin resulted in a treatment option that would provide a slightly higher effectiveness (0.019 QALY) and lower overall associated costs (-€42). In the additional analyses, dapagliflozin was a cost-effective option compared with sulphonylureas and thiazolidinediones resulting in a cost per QALY gained of €3,560 and €2,007, respectively. The univariate and probabilistic sensitivity analyses confirmed the robustness of the results. CONCLUSIONS: The results of the analyses performed suggested that dapagliflozin, in combination with metformin, would be a cost-effective alternative in the Spanish context for the treatment of T2DM.