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BACKGROUND: The DAPA-CKD study showed that dapagliflozin added to standard treatment reduced the risk of chronic kidney disease progression, and death from renal or cardiovascular causes compared to placebo. OBJECTIVE: Assess the cost-effectiveness of dapagliflozin and standard treatment versus standard treatment alone for chronic kidney disease within the Colombian health system. METHODS: We employed a Markov model based on the DAPA-CKD study, tailored to the Colombian scenario. The model forecasted hospitalizations for heart failure, overall and cardiovascular mortality, and chronic kidney disease progression over a 10-year horizon with a 5% discount rate. RESULTS: Dapagliflozin combined with standard treatment is a cost-effective intervention in treating stage 2-4 CKD. In the base case, the ICER was US $5,366, below 1 GDP (US $6.558) per capita. This was consistent in the sensitivity analyses. CONCLUSION: Our study showed that dapagliflozin, when combined with standard treatment, is cost-effective against standard treatment alone, aligning with Colombia's willingness-to-pay threshold.
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AIM: To assess the acute effect of empagliflozin versus dapagliflozin administration on flow-mediated vasodilation in patients with type 2 diabetes mellitus. DESIGN: A double-blind clinical trial, at the Experimental and Clinical Therapeutics Institute, University Health Sciences Center, at the Universidad de Guadalajara, in inpatients with T2D according to the 2023 ADA criteria. METHODS: Thirty patients (15 males and 15 females), aged between 35 and 65 years, were included in this study, according to the 2023 ADA criteria. The eligible patients were randomly assigned to three groups: empagliflozin 25 mg once daily, dapagliflozin 10 mg once daily, or placebo once daily. Anthropometric parameters were taken using validated techniques. FMD was measured using a high-resolution semiautomatic ultrasound UNEX-EF 38G (UNEX Co., Ltd., Nagoya, Japan). Arterial tension was determined with the OMRON electronic digital sphygmomanometer (HEM 907 XL, Kyoto, Japan). RESULTS: The group of patients who received empagliflozin had a significantly lower baseline flow-mediated dilation (FMD) compared to the group receiving dapagliflozin (p = 0.017); at the end of this study, the empagliflozin group achieved a comparable FMD to the dapagliflozin group (p = 0.88). CONCLUSION: After the treatment period, the empagliflozin and dapagliflozin groups achieved similar FMD, suggesting a class effect.
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INTRODUCTION: The evidence supporting pharmacological heart failure treatment relies on randomized clinical trials with stringent inclusion and exclusion criteria. OBJECTIVES: Assess the eligibility of outpatients with chronic heart failure for the trials DAPA-HF, EMPEROR-reduced, and PARADIGM-HF, while exploring potential differences among study populations. METHODS: By reviewing medical records, we determined the eligibility rate for each study and evaluated the incidence of heart failure hospitalizations and all-cause mortality during this period. RESULTS: A total of 446 patients were included in the cohort. Approximately 75% would be ineligible for the trials, mainly because of their comorbidities. Ineligible patients had a higher all-cause mortality, but a similar incidence of hospitalization. CONCLUSION: Approximately 1 in 4 patients from a heart failure clinic in Medellin, Colombia would meet the eligibility criteria for the DAPA-HF, EMPEROR-reduced, and PARADIGM-HF trials. These findings highlight the need to complement randomized clinical trials with real-world data.
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Cardiologia , Insuficiência Cardíaca , Humanos , Valsartana/uso terapêutico , Volume Sistólico , Tetrazóis/efeitos adversos , Estudos Retrospectivos , Colômbia/epidemiologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Combinação de Medicamentos , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/terapiaRESUMO
Resumen La insuficiencia cardiaca aguda es una emergencia que aumenta la mortalidad cardiovascular debido a los síntomas y signos de congestión e hipoperfusión vascular. El manejo actual con diuréticos, inotrópicos y vasopresores mejora el estado clínico; sin embargo, la morbimortalidad asociada a esta patología sigue siendo altamente significativa. Por otra parte, los inhibidores del cotransportador sodio-glucosa tipo 2 (iSGLT2) han demostrado una reducción en la hospitalización y mortalidad cardiovascular en los pacientes con insuficiencia cardiaca crónica. Por ende, el objetivo de este artículo es analizar los efectos clínicos de este grupo farmacológico en la insuficiencia cardiaca aguda, con base en investigaciones científicas. Los hallazgos de estas investigaciones demostraron un beneficio clínico de los iSGLT2 sobre esta patología, con base a parámetros como mortalidad, hospitalización, eventos clínicos, función renal, efecto diurético y concentraciones del biomarcador NT-proBnp, los cuales se detallarán en el presente artículo. Por consiguiente, se concluyó que estos fármacos son seguros sobre la evolución clínica de la insuficiencia cardiaca aguda.
Abstract Acute heart failure is an emergency that increases cardiovascular mortality due to symptoms and signs of vascular congestion and hypoperfusion. Current management with diuretics, inotropes, and vasopressors improves the clinical status; However, the morbidity and mortality associated with this pathology remains highly significant. On the other hand, sodium-glucose cotransporter 2 (SGLT2i) inhibitors have shown a reduction in hospitalization and cardiovascular mortality in patients with chronic heart failure. Therefore, the objective of this article is to analyze the clinical effects of this pharmacological group in acute heart failure, based on scientific research. The findings of these investigations demonstrated a clinical benefit of SGLT2i on this pathology, based on parameters such as mortality, hospitalization, clinical events, renal function, diuretic effect and concentrations of the NTproBnp biomarker, which will be detailed in this article. Therefore, it was concluded that these drugs are safe on the clinical course of acute heart failure.
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Humanos , Masculino , Feminino , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológicoRESUMO
Sodium glucose cotransporter 2 inhibitors (SGLT2) have been increasingly pursued as a promising target for addressing residual cardiovascular risk. Prior trials demonstrated that SGLT2i not only promotes glucose-lowering, but also improves endothelial dysfunction, adiposity, fluid overload, and insulin sensitivity thus contributing to hemodynamic changes implicated in its cardiorenal benefits. The mechanisms in the effect of SGLT2i on blood pressure and their potential role in preventing cardiovascular events are hereby revised.
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SGLT2 inhibitors (SGLT2i) are now the mainstay therapy for both diabetes and heart failure. Post-hoc publications, meta-analysis, and conference presentations of the eight SGLT2i Cardiovascular Outcomes trials (CVOTS) done in diabetic patients constantly echo that this class of drug decreases mortality, reduces cardiovascular events, and prevents heart failure and kidney disease. This review of medical agencies' SGLT2i analysis (FDA and EMA) helps to understand the reality of SGLT2i results in those trials, avoiding to consider observational and statistically undemonstrated endpoints as validated. They also confirmed the unique diuretic mode of action of SGLT2i, promoting osmotic diuresis, and its potential adverse events secondary to hypovolemia and hematocrit increase. They also support the understanding that the beliefs in SGLT2i morbi-mortality benefits are largely overstated mostly based on undemonstrated endpoints. Finally, it is clear that SGLT2i's antidiabetic action, secondary to its renal mode of action, plateaued after a few months and decreased strongly over time, questioning its long-term goal of maintaining diabetic patients' HbA1c below 7%. Also, this effect in patients with renal impairment is quasi null. We think that this review would be very helpful to every physician treating diabetic patients to better balance belief and reality of SGLT2i prescription effects.
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Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diuréticos/uso terapêutico , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/complicações , Estudos Observacionais como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversosRESUMO
One of the most relevant and differentiating aspects provided by the 2021 European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic heart failure is the retraction of the historical stepped and vertical pharmacological treatment scheme for heart failure with reduced ejection fraction (HFrEF). Subsequently, it was replaced by an updated algorithm that places four therapeutic families in the same initial horizontal step with an equally high degree of recommendation (class I). In this context, these four pillars, which have demonstrated a significant reduction in mortality and hospitalizations in patients with HFrEF, include (1) angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB)/angiotensin II receptor-neprilysin inhibitors (ARNi), (2) beta blockers, (3) mineralocorticoid receptor antagonists (MRA) and (4) sodium-glucose cotransporter 2 inhibitors (SGLT2is) as the main novelty. This manuscript reviews the current therapeutic algorithm with a special focus on the therapeutic value of adding an MRA (still underused in both clinical trials and real world), changing an ACEi/ARB for an ARNi and incorporating an SGLT2i in patients with HFrEF. This article is part of the Emerging concepts in heart failure management and treatment Special Issue: https://www.drugsincontext.com/special_issues/emerging-concepts-in-heart-failure-management-and-treatment.
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Clinical trials have shown that sodium glucose co-transporter 2 (SGLT2) inhibitors improve clinical outcomes in diabetes mellitus (DM) patients. As most studies were performed in Type 2 DM, the cardiovascular effects of SGLT2 inhibition still require clarification in Type 1 DM. We analyzed the effects of SGLT2 inhibitor dapagliflozin on cardiac remodeling in rats with streptozotocin-induced diabetes, an experimental model of Type 1 DM. Methods: Male Wistar rats were assigned into four groups: control (C, n = 14); control treated with dapagliflozin (C + DAPA, n = 14); diabetes (DM, n = 20); and diabetes treated with dapagliflozin (DM + DAPA, n = 20) for 8 weeks. Dapagliflozin dosage was 5 mg/kg/day. Statistical analyses: ANOVA and Tukey or Kruskal−Wallis and Dunn. Results: DM + DAPA presented decreased blood pressure and glycemia and increased body weight compared to DM (C 507 ± 52; C + DAPA 474 ± 50; DM 381 ± 52 *; DM + DAPA 430 ± 48 # g; * p < 0.05 vs. C; # p < 0.05 vs. C + DAPA and DM + DAPA). DM echocardiogram presented left ventricular and left atrium dilation with impaired systolic and diastolic function. Cardiac changes were attenuated by dapagliflozin. Myocardial hydroxyproline concentration and interstitial collagen fraction did not differ between groups. The expression of Type III collagen was lower in DM and DM + DAPA than their controls. Type I collagen expression and Type I-to-III collagen ratio were lower in DM + DAPA than C + DAPA. DM + DAPA had lower lipid hydroperoxide concentration (C 275 ± 42; C + DAPA 299 ± 50; DM 385 ± 54 *; DM + DAPA 304 ± 40 # nmol/g tissue; * p < 0.05 vs. C; # p < 0.05 vs. DM) and higher superoxide dismutase and glutathione peroxidase activity than DM. Advanced glycation end products did not differ between groups. Conclusion: Dapagliflozin is safe, increases body weight, decreases glycemia and oxidative stress, and attenuates cardiac remodeling in an experimental rat model of Type 1 diabetes mellitus.
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INTRODUCTION: SGLT2 inhibitors or DPP-4 inhibitors are among the preferred options in patients with type 2 diabetes mellitus (T2DM) without established cardiovascular disease. OBJECTIVE: To evaluate the incremental cost-effectiveness of dapagliflozin versus DPP-4 inhibitors as a complement to metformin in the treatment ofT2D, from the perspective of the Colombian health system. METHODS: The Cardiff model was used to estimate the incremental cost-effectiveness ratio (ICER) of dapagliflozin plus metformin compared to DPP-4 inhibitors plus metformin in adults with T2DM who did not respond adequately to metformin monotherapy. We estimated the incidence of micro- and macrovascular complications from risk equations incorporating the effect of treatment. The time horizon for analysis was 5 years and a discount rate of 5% was applied, for both costs and outcomes. The costs were expressed in 2020 USD (1 USD = $3,693.36 COP). RESULTS: Dapagliflozin in association with metformin resulted in a higher number of quality-adjusted life years (QALYs) compared to the intervention. The ICER was US$1,964.80 per QALY gained. CONCLUSION: From the point of view of Colombian healthcare system, the combination of dapagliflozin with metformin is a cost-effective option compared to DPP-4 + metformin inhibitors in the treatment of T2D without established cardiovascular disease.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Metformina , Compostos Benzidrílicos , Colômbia , Análise Custo-Benefício , Quimioterapia Combinada , Glucosídeos , Humanos , Hipoglicemiantes , Anos de Vida Ajustados por Qualidade de VidaRESUMO
INTRODUCTION: The DAPA-HF study has shown that dapagliflozin added to standard treatment reduced the risks of worsening of heart failure or cardiovascular death compared to placebo. OBJECTIVES: To evaluate the cost- utility of dapagliflozin in combination with standard treatment compared to standard treatment alone for the treatment of heart failure with reduced ejection fraction from the perspective of the Colombian health system. METHODS: A Markov model using information from the DAPA-HF study was adapted to the Colombian setting. Health states considered symptom score, and transient health states were included to assess the incidence of consultations and hospitalizations for heart failure. The time horizon was 5 years and a 5% discount rate was applied. The costs were expressed in US dollars of 2020 (1 USD =$3,693.36 COP). RESULTS: The incremental cost-effectiveness ratio (ICER) of the intervention compared to standard treatment was USD $5,946 per quality adjusted life year gained. The ICER remained below the cost-effectiveness threshold in sub-group analyses. 97% of sensitivity analysis simulations showed an ICER below the cost-effectiveness threshold. CONCLUSION: From the perspective of the analysis, the addition of dapagliflozin to standard treatment is a cost-effective option in patients with heart failure with reduced ejection fraction in Colombia.
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Insuficiência Cardíaca , Compostos Benzidrílicos , Colômbia , Análise Custo-Benefício , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/terapia , Humanos , Volume SistólicoRESUMO
INTRODUCTION: This prospective pharmacodynamic (PD) study assessed the effect of the sodium-glucose co-transporter-2 inhibitor (SGLT2i), dapagliflozin, on platelet reactivity. METHODS: Patients with stable coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) (n = 27) who were on maintenance dual antiplatelet therapy (DAPT) of aspirin 81 mg daily, and clopidogrel 75 mg daily were recruited. Platelet function was evaluated with the VerifyNow™ P2Y12 assay (Werfen, Bedford, MA, USA) and assessed prior to initiation of and after 10 days of treatment with dapagliflozin 10 mg once-daily dose regimen. Results were compared with a paired t test. RESULTS: Treatment with dapagliflozin significantly decreased P2Y12 reaction units (PRU) by 20%, (95% confidence interval (CI) 8.5-32.6%, p value 0.002). The mean difference in PRU was 36.70 (95% CI 16.66-56.75). No patients experienced any serious adverse events (SAEs). CONCLUSIONS: Significantly diminished platelet reactivity was observed on dapagliflozin as compared to without dapagliflozin. This dedicated pharmacodynamic study could be potentially informative and applicable for Trinidadian stable CAD patients with T2DM on DAPT. Further studies are required to confirm these exploratory findings. CLINICAL TRIAL REGISTRATION: EDGE ClinicalTrials.gov number NCT04400760.
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BACKGROUND: Heart failure (HF) prognosis without therapy is poor, however introduction of a range of drugs has improved it. We aimed to perform a systematic review on the effects and safety of sodium-glucose transporter 2 inhibitors (SGLT2i) in HF patients. METHODS: We carried out a systematic review of randomized controlled trials (RCTs) on SGLT2i compared to placebo for HF patients. We searched in PubMed, Scopus, Web of Science and EMBASE, with no language restriction, from inception to 31 August 2020. We included nine RCTs comprising three arms (empagliflozin, dapagliflozin and placebo). Effects sizes for continuous variables were expressed as mean differences (MDs) and 95% confidence intervals (CIs). Effects sizes for dichotomous variables were expresses as risk ratio (RR) and 95% CIs. We used random-effect models with the inverse variance method. We performed subgroup meta-analyses by intervention drug and follow-up period. RESULTS: SGLT2i significantly reduced all-cause mortality (RR: 0.88, 95%CI 0.79-0.98, I2 = 0%), cardiovascular mortality (RR: 0.87, 95%CI 0.77-0.99, I2 = 0%), HF hospitalization (RR: 0.73, 95%CI 0.66-0.81, I2 = 0%) and emergency room visits due to HF (RR: 0.40, 95%CI 0.21-0.76, I2 = 0%), as well as composite outcomes including the previous ones. Besides, it significantly improved the score of the Kansas City Cardiomyopathy Questionnaire (KCCQ, MD: 1.70, 95%CI 1.67-1.73, I2 = 54%). SGLT2i reduced any serious adverse events, blood pressure and weight. However, it increased hematocrit and creatinine. The meta-analysis of RCTs of > 12 weeks of follow-up showed that SGTL2i significantly reduced NT-proBNP. CONCLUSIONS: SGLT2i showed to improve critical outcomes in HF patients, and it is apparently safe.
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Gliflozins (canagliflozin, dapagliflozin and empagliflozin) are the newest anti-hyperglycemic class and have offered cardiovascular and renal benefits. Because platelets are involved in the atherothrombosis process, this study is aimed to evaluate the direct effect of gliflozins on platelet reactivity. Platelet-rich plasma (PRP) or washed platelets (WP) were obtained from healthy volunteers. Aggregation, flow cytometry for glycoprotein IIb/IIIa, cyclic nucleotides and intracellular calcium levels, Western blot, thromboxane B2 (TXB2) measurement and COX-1 activity were performed in the presence of gliflozins (1-30 µM) alone or in combination with sodium nitroprusside (SNP, 10 or 100 nM) + iloprost (ILO, 0.1 or 1 nM). SGLT2 protein is not expressed on human platelets. Gliflozins produced little inhibitory effect in agonists-induced aggregation and this effect was greatly potentiated by ~10-fold in the presence of SNP + ILO, accompanied by lower levels of TXB2 (58.1 ± 5.1%, 47.1 ± 7.2% and 43.4 ± 9.2% inhibition for canagliflozin, dapagliflozin and empagliflozin, respectively). The activity of COX-1 was not affected by gliflozins. Collagen increased Ca2+ levels and α(IIb)ß(3) activation, both of which were significantly reduced by gliflozins + SNP + ILO. The intracellular levels of cAMP and cGMP and the protein expression of p-VASPSer157 and p-VASPSer239 were not increased by gliflozins while the expression of the serine-threonine kinase, AktSer473 was markedly reduced. Our results showed that the antiplatelet activity of gliflozins were greatly enhanced by nitric oxide and prostacyclin, thus suggesting that the cardiovascular protection seen by this class of drugs could be in part due to platelet inhibition.
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Epoprostenol/administração & dosagem , Óxido Nítrico/administração & dosagem , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Adulto , Células Cultivadas , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/fisiologia , Transportador 2 de Glucose-Sódio/metabolismo , Adulto JovemRESUMO
Steatosis, a condition characterized by excessive lipid deposition. Although usually a benign condition, steatosis mays progress to cirrhosis or hepatocellular carcinoma. Recent evidence suggests that SGLT2 inhibitors suppress the development of nonalcoholic steatohepatitis in humans, as well as in rodent models and that SGLT2 inhibitors alleviate hepatic steatosis or steatohepatitis in obese type 2 diabetic rats or mice. 14 Patients with nonalcoholic fatty liver disease used a fixed dose of 10 mg of dapagliflozin for an average of 75 days. ALT, AST, GGT, insulin, HOMA-IR, and weight levels were significantly lower after treatment. There was no significant correlation between the reduction in HOMA and the reduction in ALT values or weight reduction obtained during treatment and ALT values.
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In patients with urinary magnesium wasting, oral and intravenous supplementation often fail to adequately improve serum magnesium levels. Glucose intolerance and diabetes mellitus frequently accompany hypomagnesemia. Clinical trials examining inhibitors of the type 2 sodium glucose cotransporter (SGLT2) show small but significant increases in serum magnesium levels in diabetic patients. This report describes dramatic improvement in serum magnesium levels and associated symptoms after initiating SGLT2 inhibitor therapy in 3 patients with refractory hypomagnesemia and diabetes. Each patient received a different SGLT2 inhibitor: canagliflozin, empagliflozin, or dapagliflozin. One patient discontinued daily intravenous magnesium supplements and exhibited higher serum magnesium levels than had been achieved by magnesium infusion. 2 of the 3 patients exhibited reduced urinary fractional excretion of magnesium, suggesting enhanced tubular reabsorption of magnesium. These observations demonstrate that SGLT2 inhibitors can improve the management of patients with otherwise intractable hypomagnesemia, representing a new tool in this challenging clinical disorder.
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Resumen: El Congreso Europeo de Cardiología constituye uno de los eventos más relevantes de la comunidad cardiológica mundial. Fue realizado entre el 31 de agosto y el 4 de setiembre en el corazón de París, siendo el tema central la salud cardiovascular global. Como es habitual, contó con la presencia de más de 30.000 profesionales y destacados invitados. Se presentaron actualizaciones de varias guías de práctica clínica e importantes trabajos científicos que sin duda impactarán en el tratamiento de los pacientes con patología cardiovascular. A continuación realizaremos un breve resumen de algunos de los trabajos presentados: - A trial to evaluate the effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in patients with heart failure and reduced left ventricular ejection fraction: DAPA-HF - Complete revascularization with multivessel PCI for myocardial infarction: the COMPLETE Trial - Angiotensin-neprylysin inhibition in heart failure with preserved ejection fraction: the PARAGON-HF - Antithrombotic therapy for atrial fibrillation with stable coronary disease: the AFIRE Investigators - Ticagrelor or prasugrel in patients with acute coronary syndromes: the ISAR-REACT 5 Trial
Summary: The European Congress of Cardiology is one of the most relevant events of the world cardiology community. It was held from August 31 to September 4 in the heart of Paris, France, the central theme being global cardiovascular health. As usual, it was attended by more than 30,000 professionals and prominent guests. Updates of several clinical practice guides and important scientific papers were presented. These undoubtedly will impact in the treatment of patients with cardiovascular pathology. Below we present a brief summary of some of the trials presented: - A trial to evaluate the effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in patients with heart failure and reduced left ventricular ejection fraction: DAPA-HF - Complete revascularization with multivessel PCI for myocardial infarction: the COMPLETE Trial - Angiotensin-neprylysin inhibition in heart failure with preserved ejection fraction: the PARAGON-HF - Antithrombotic therapy for atrial fibrillation with stable coronary disease: the AFIRE Investigators - Ticagrelor or prasugrel in patients with acute coronary syndromes: the ISAR-REACT 5 Trial
Sumário: O Congresso Europeu de Cardiologia é um dos eventos mais relevantes da comunidade mundial de cardiologia. Foi realizada de 31 de agosto ao 4 de setembro no coração de Paris, na França, o tema central foi a saúde cardiovascular global. Como sempre, participaram mais de 30.000 profissionais e convidados de destaque. Atualizações de vários guias de prática clínica e importantes artigos científicos foram apresentados que, sem dúvida, impactarão o tratamento de pacientes com patologia cardiovascular. Abaixo, faremos um breve resumo de alguns trials apresentados: - A trial to evaluate the effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in patients with heart failure and reduced left ventricular ejection fraction: DAPA-HF - Complete revascularization with multivessel PCI for myocardial infarction: the COMPLETE Trial - Angiotensin-neprylysin inhibition in heart failure with preserved ejection fraction: the PARAGON-HF - Antithrombotic therapy for atrial fibrillation with stable coronary disease: the AFIRE Investigators - Ticagrelor or prasugrel in patients with acute coronary syndromes: the ISAR-REACT 5 Trial
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A simple, sensitive, precise, accurate and robust high performance liquid chromatographic method has been developed for simultaneous estimation of saxagliptin (SAXA) and dapagliflozin (DAPA) in pharmaceutical formulation. Design of experiments (DoE) was applied for multivariate optimization of the experimental conditions of RP-HPLC method. Risk assessment was performed to identify the critical method parameters. Three independent factors; mobile phase composition, flow rate and column temperature were used to design mathematical models. Central composite design (CCD) was used to study the response surface methodology and to study in depth the effects of these independent factors. Desirability function was used to simultaneously optimize the retention time and resolution of SAXA and DAPA. The optimized and predicted data from contour diagram consisted of acetonitrile and ortho phosphoric acid (0.1%) in the ratio of 50:50 respectively, at a flow rate of 0.98 ml/min and column temperature 31.4 °C. Using these optimum conditions baseline separation of both drugs with good resolution and run time of less than 6 min were achieved. The optimized assay conditions were validated according to ICH guidelines. Hence, the results clearly showed that Quality by design approach could be successfully applied to optimize RP-HPLC method for simultaneous estimation of SAXA and DAPA.
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Preparações Farmacêuticas/classificação , Cromatografia Líquida de Alta Pressão/métodos , Diabetes Mellitus Tipo 2/classificação , Comprimidos/administração & dosagem , Formas de Dosagem , Otimização de Processos/métodosRESUMO
ABSTRACT Objective: This analysis compared the efficacy and safety of the sodium-glucose cotransporter-2 (SGLT2) inhibitor, dapagliflozin, and the dipeptidyl peptidase-4 (DPP4) inhibitor, saxagliptin, both added on to metformin. Materials and methods: This was a post-hoc analysis from a double-blind, randomized, 24-week clinical trial (NCT01606007) of patients with type 2 diabetes (T2D) inadequately controlled with metformin. We compared the dapagliflozin 10 mg (n = 179) and saxagliptin 5 mg (n = 176) treatment arms. Results: Dapagliflozin showed significantly greater mean reductions versus saxagliptin in HbA1c (difference versus saxagliptin [95% CI]: −0.32% [-0.54, −0.10]; p < 0.005), fasting plasma glucose (-0.98 [-1.42, −0.54] mmol/L; p < 0.0001), body weight (-2.39 [-3.08, −1.71] kg; p < 0.0001) and systolic blood pressure (SBP) (-3.89 [-6.15, −1.63] mmHg; p < 0.001). More dapagliflozintreated than saxagliptin-treated patients achieved the composite endpoint of HbA1c reduction ≥ 0.5%, weight loss ≥ 2 kg, SBP reduction ≥ 2 mmHg and no major/minor hypoglycemia (24% versus 7%). No major events of hypoglycemia were reported. More patients on dapagliflozin (6%) versus saxagliptin (0.6%) experienced genital infections. Conclusion: Dapagliflozin demonstrated greater glycemic efficacy than saxagliptin with additional benefits on weight and SBP, and the safety profile was consistent with previous studies.
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Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Compostos Benzidrílicos/uso terapêutico , Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glucosídeos/uso terapêutico , Compostos Benzidrílicos/efeitos adversos , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Adamantano/efeitos adversos , Adamantano/uso terapêutico , Método Duplo-Cego , Diabetes Mellitus Tipo 2/sangue , Dipeptídeos/efeitos adversos , Transportador 2 de Glucose-Sódio/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêuticoRESUMO
Los inhibidores del cotransportador sodio-glucosa tipo 2 son un grupo de fármacos que se utilizan en tratamiento de la diabetes tipo 2. Un efecto adverso que pueden producir es la cetoacidosis diabética euglucémica, una entidad clínica que se debe conocer para realizar el adecuado diagnóstico y tratamiento, suspendiendo la administración de dichos fármacos.
Inhibitors of sodium-glucose cotransporter type 2 are a group of drugs used in treatment of type 2 diabetes. Euglycemic diabetic ketoacidosis is an adverse effect that may occur and a clinical entity that should be known for proper diagnosis and treatment, suspending the administration of this medication.
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Humanos , Feminino , /complicações , Cetoacidose Diabética/complicações , Cetoacidose Diabética/diagnóstico , /efeitos adversos , Preparações FarmacêuticasRESUMO
Dapaglifozina, un inhibidor del cotransportador de sodio-glucosa 2 (I-SGLT2) induce glucosuria y reduce la glicemia en adultos con diabetes tipo 2. Objetivo: Presentar una cetosis diabética normoglicémica en una adolescente con diabetes tipo 1 (DM1) que recibía dapaglifozina y alertar sobre el riesgo del uso I-SGLT2 que parece promisorio, pero no está aprobado en niños ni en DM1. Caso clínico: Paciente de 17 años sin cetosis durante 9 años con DM1, inició dapaglifozina 10 mg/día para reducir la insulina y el peso. Durante 11 meses de tratamiento tuvo cetonas capilares indetectables, redujo el índice de masa corporal 23,9 a 21,1 kg/m², la insulina basal 40 a 17 U, la hemoglobina glicosilada 8,3 a 7,5%, la glicemia capilar 175 a 161 mg/dl y la variabilidad de la glucosa (desvío estándar 85 a 77). Inesperadamente aparecieron náuseas y vómitos. La paciente portaba bomba de insulina con monitorización continua de glucosa, bien calibrada (glucosas intersticiales concordantes con glicemias), que mostraba glucosa estable bajo 200 mg/dl. Recibió insulina pero los vómitos persistieron; en tres horas, aparecieron deshidratación y desmayos, con cetonas 4,6 nmol/l y glicemia 224 mg/dl. Recibió suero fisiológico, ondansetrón, carbohidratos y varias dosis de insulina con pronta recuperación del estado general e hidratación, sin embargo, la cetosis continuó durante 24 horas. Cabe destacar que la bomba estaba funcionando bien y no se cambió la cánula. Al superar la cetosis, continuó con la misma cánula con buen control metabólico. Conclusión: Es importante sospechar la cetosis diabética normoglicémica por ser de riesgo vital.
Dapagliflozin, an insulin-independent sodium-glucose cotransporter 2 inhibitor (SGLT2-I) induces glycosuria and reduces hyperglycemia in adults with type 2 diabetes. Objective: To present an euglycemic diabetic ketosis in an adolescent with type 1 diabetes (T1D) receiving dapagliflozin, to alert about the risk of a drug not approved in children nor in T1D. Case report: A 17 years old adolescent with T1D during 9 years, was started on dapagliflozin 10 mg / day to reduce insulin dose and weight. During 11 months on treatment, capillaries ketones were undetectable and she exhibited a reduction in body mass index 23.9 to 21.1 kg/m2, basal insulin 40 to 17 U, glycated hemoglobin 8.3 to 7.5%, capillary glucose 175 to 161 mg/dl and glucose variability (standard deviation) 85 to 77. Suddenly nausea and vomits appeared. The patient was on an insulin pump and well calibrated continuous glucose monitoring, showing stable glucose levels under 200 mg/dl, and an insulin bolus was delivered. Vomiting without hyperglycemia persisted; three hours later, she was severely dehydrated and fainting, with ketones 4.6 nmol/l and glucose 224 mg/dl. She received IV saline fluids, ondansetron, carbohydrates and several insulin boluses. Hydration and general condition improved soon, however despite several insulin doses, ketosis continued for 24 hours. It is remarkable that the pump was working well and the cannula was not changed. After the ketosis was resolved, she continued using the same cannula with good metabolic control. Conclusion: Euglycemic ketosis is a life-threatening condition that must be suspected.