RESUMO
BACKGROUND: For patients using basal-bolus insulin therapy, it is widespread clinical practice to aim for a 50-50 ratio between basal and total daily bolus. However, this practice was based on a small study of individuals without diabetes. To assess the rule in real-world practice, we retrospectively analyzed patients on basal-bolus therapy that was adjusted at least weekly by an artificial intelligence-driven titration within the d-Nav® Insulin Management Technology. MATERIALS AND METHODS: We obtained de-identified data from the Diabetes Centre of Ulster Hospital for patients with four inclusion criteria: type 2 Diabetes (T2D), on d-Nav >6 months, on basal-bolus insulin therapy >80% of the time (based on insulin analogs), and no gap in data >3 months. RESULTS: We assembled a cohort of 306 patients, followed by the d-Nav service for 3.4 ± 1.8 years (mean ± SD), corresponding to about 180 autonomous insulin dose titrations and about 5000 autonomous individual dose recommendations per patient. After an initial run-in period, mean glycated hemoglobin (HbA1c) values in the cohort were maintained close to 7%. Surprisingly, in just over three-quarters of the cohort, the average basal insulin fraction was <50%; in half of the cohort average basal insulin fraction <41.2%; and in one-quarter the basal insulin fraction was <33.6%. Further, the basal insulin fraction did not remain static over time. In half of the patients, the basal insulin fraction varied by ≥1.9×; and, in 25% of the patients, ≥2.5×. CONCLUSION: Our data show that a 50-50 ratio of basal-to-bolus insulin does not generally apply to patients with T2D who successfully maintain stable glycemia. Therefore, the 50-50 ratio should not serve as an ongoing treatment guide. Moreover, our results emphasize the importance of at least weekly insulin titrations.
Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/induzido quimicamente , Hipoglicemiantes/uso terapêutico , Insulina Glargina/uso terapêutico , Controle Glicêmico , Estudos Retrospectivos , Inteligência Artificial , Glicemia , Resultado do Tratamento , Insulina/uso terapêuticoRESUMO
BACKGROUND: Insulin therapy is most effective if dosage titrations are done regularly and frequently, which is seldom practical for most clinicians, resulting in an insulin titration gap. The d-Nav Insulin Guidance System (Hygieia, Livonia, MI, USA) is a handheld device that is used to measure glucose, determine glucose patterns, and automatically determine the appropriate next insulin dose. We aimed to determine whether the combination of the d-Nav device and health-care professional support is superior to health-care professional support alone. METHODS: In this multicentre, randomised, controlled study, we recruited patients from three diabetes centres in the USA (in Detroit MI; Minneapolis, MN; and Des Moines IA). Patients were eligible if they were aged 21-70 years, diagnosed with type 2 diabetes with a glycated haemoglobin (HbA1c) concentration of 7·5% or higher (≥58 mmol/mol) and 11% or lower (≤97 mmol/mol), and had been using the same insulin regimen for the previous 3 months. Exclusion criteria included body-mass index of 45 kg/m2 or higher; severe cardiac, hepatic, or renal impairment; and more than two severe hypoglycaemic events in the past year. Eligible participants were randomly assigned (1:1), with randomisation blocked within each site, to either d-Nav and health-care professional support (intervention group) or health-care professional support alone (control group). Both groups were contacted seven times (three face-to-face and four phone visits) during 6 months of follow-up. The primary objective was to compare average change in HbA1c from baseline to 6 months. Safety was assessed by the frequency of hypoglycaemic events. The primary objective and safety were assessed in the intention-to-treat population. We used Student's t test to assess the primary outcome for statistical significance. This study was registered with ClinicalTrials.gov, number NCT02424500. FINDINGS: Between Feb 2, 2015, and March 17, 2017, 236 patients were screened for eligibility, of whom 181 (77%) were enrolled and randomly assigned to the intervention (n=93) and control (n=88) groups. At baseline, mean HbA1c was 8·7% (SD 0·8; 72 mmol/mol [SD 8·8]) in the intervention group and 8·5% (SD 0·8; 69 mmol/mol [SD 8·8]) in the control group. The mean decrease in HbA1c from baseline to 6 months was 1·0% (SD 1·0; 11 mmol/mol [SD 11]) in the intervention group, and 0·3% (SD 0·9; 3·3 mmol/mol [9·9]) in the control group (p<0·0001). The frequency of hypoglycaemic events per month was similar between the groups (0·29 events per month [SD 0·48] in the intervention group vs 0·29 [SD 1·12] in the control group; p=0·96). INTERPRETATION: The combination of automated insulin titration guidance with support from health-care professionals offers superior glycaemic control compared with support from health-care professionals alone. Such a solution facilitated safe and effective insulin titration in a large group of patients with type 2 diabetes, and now needs to be evaluated across large health-care systems to confirm these findings and study cost-effectiveness. FUNDING: US National Institutes of Health, National Institute of Digestive and Kidney Diseases.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Sistemas de Liberação de Medicamentos/instrumentação , Hemoglobinas Glicadas/metabolismo , Insulina/uso terapêutico , Conduta do Tratamento Medicamentoso/tendências , Idoso , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Hemoglobinas Glicadas/análise , Pessoal de Saúde , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
Insulin therapy is mainly used by people with type 2 diabetes who have failed other therapies and have become insulin-deficient. This group represents about a quarter of all people with type 2 diabetes. Almost all those with type 2 diabetes who start insulin therapy or intensify it gain weight, which may potentially diminish the prognostic advantage of improved glycaemia. To date, all available guidelines emphasize both the attainment of glycated haemoglobin (HbA1c) goals and weight control, without directing the clinician as to which element is of a higher priority. The following review attempts to clarify the issue using the available literature. The body of evidence presented in this review indicates that glycaemic management with exogenous insulin replacement is of a much higher priority than weight gain. Lower weight or weight loss do not show prognostic benefit in advanced stages of diabetes; therefore, weight gain should not discourage providers from achieving and maintaining HbA1c goals with insulin therapy, regardless of insulin dosage or other medications.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas/análise , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Aumento de Peso/fisiologia , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , PrognósticoRESUMO
OBJECTIVE: Few randomized controlled trials have focused on the optimal management of patients with type 2 diabetes (T2D) during the transition from the inpatient to outpatient setting. This multicenter open-label study explored a discharge strategy based on admission hemoglobin A1c (HbA1c) to guide therapy in general medicine and surgery patients with T2D. METHODS: Patients with HbA1c ≤7% (53 mmol/mol) were discharged on sitagliptin and metformin; patients with HbA1c between 7 and 9% (53-75 mmol/mol) and those >9% (75 mmol/mol) were discharged on sitagliptinmetformin with glargine U-100 at 50% or 80% of the hospital daily dose. The primary outcome was change in HbA1c at 3 and 6 months after discharge. RESULTS: Mean HbA1c on admission for the entire cohort (N = 253) was 8.70 ± 2.3% and decreased to 7.30 ± 1.5% and 7.30 ± 1.7% at 3 and 6 months ( P<.001). Patients with HbA1c <7% went from 6.3 ± 0.5% to 6.3 ± 0.80% and 6.2 ± 1.0% at 3 and 6 months. Patients with HbA1c between 7 and 9% had a reduction from 8.0 ± 0.6% to 7.3 ± 1.1% and 7.3 ± 1.3%, and those with HbA1c >9% from 11.3 ± 1.7% to 8.0 ± 1.8% and 8.0 ± 2.0% at 3 and 6 months after discharge (both P<.001). Clinically significant hypoglycemia (<54 mg/dL) was observed in 4%, 4%, and 7% among patients with a HbA1c <7%, 7 to 9%, and >9%, while a glucose <40 mg/dL was reported in <1% in all groups. CONCLUSION: The proposed HbA1c-based hospital discharge algorithm using a combination of sitagliptin-metformin was safe and significantly improved glycemic control after hospital discharge in general medicine and surgery patients with T2D. ABBREVIATIONS: BG = blood glucose; DPP-4 = dipeptidyl peptidase-4; eGFR = estimated glomerular filtration rate; HbA1c = hemoglobin A1c; T2D = type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Metformina/administração & dosagem , Fosfato de Sitagliptina/administração & dosagem , Adulto , Idoso , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Quimioterapia Combinada , Feminino , Hemoglobinas Glicadas/análise , Humanos , Masculino , Metformina/efeitos adversos , Pessoa de Meia-Idade , Alta do Paciente , Estudos Prospectivos , Fosfato de Sitagliptina/efeitos adversosAssuntos
Diabetes Mellitus Tipo 2 , Insulina , Hemoglobinas Glicadas/análise , Humanos , HipoglicemiantesRESUMO
Background: Despite new pharmacotherapy, most patients with long-term type 2 diabetes are still hyperglycemic. This could have been solved by insulin with its unlimited potential efficacy, but its dynamic physiology demands frequent titrations which are overdemanding. This report provides a real-life account for a scalable transformation of diabetes care in a community-based endocrinology center by harnessing artificial intelligence-based autonomous insulin titration. Methods: The center embedded the d-Nav® technology and its dedicated clinical support. Reported outcomes include treatment efficacy/safety in the first 600 patients and use of cardiorenal-risk reduction pharmacotherapy. Findings: Patients used d-Nav for 8.2 ± 3.0 months with 82% retention. Age was 67.1 ± 11.5 years and duration of diabetes was 19.8 ± 11.0 years. During the last 3 years before d-Nav, glycated hemoglobin (HbA1c) had been overall higher than 8% and at the beginning of the program it was as high as 8.6% ± 2.1% with 29.3% of the patients with HbA1c >9%. With d-Nav, HbA1c decreased to 7.3% ± 1.2% with 5.7% of patients with HbA1c >9%. During the first 3 months, d-Nav reduced total daily dose of insulin in one of every five patients due to relatively low glucose levels to minimize the risk of hypoglycemia. Glucagon like peptide 1 (GLP-1) receptor agonists or dual GLP-1 and Glucose-dependent insulinotropic polypeptide (GIP) receptor agonists were prescribed in about a half of the patients and sodium glucose cotransporter 2 inhibitor in a third. The frequency of hypoglycemia (<54 mg/dL) was 0.4 ± 0.6/month and severe hypoglycemia 1.7/100-patient-years. Interpretation: The use of d-Nav allowed for improvement in overall diabetes management with appropriate use of both insulin and noninsulin pharmacologic agents in a scalable way.
Assuntos
Inteligência Artificial , Glicemia , Diabetes Mellitus Tipo 2 , Hemoglobinas Glicadas , Hipoglicemiantes , Insulina , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/administração & dosagem , Idoso , Feminino , Masculino , Insulina/uso terapêutico , Insulina/administração & dosagem , Pessoa de Meia-Idade , Hemoglobinas Glicadas/análise , Glicemia/análise , Glicemia/efeitos dos fármacos , Hipoglicemia/prevenção & controleRESUMO
It has previously been shown that misfolded mutant Akita proinsulin in the endoplasmic reticulum engages directly in protein complexes either with nonmutant proinsulin or with "hProCpepGFP" (human proinsulin bearing emerald-GFP within the C-peptide), impairing the trafficking of these "bystander" proinsulin molecules (Liu, M., Hodish, I., Rhodes, C. J., and Arvan, P. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 15841-15846). Herein, we generated transgenic mice, which, in addition to expressing endogenous proinsulin, exhibit beta-cell-specific expression of hProCpepGFP via the Ins1 promoter. In these mice, hProCpepGFP protein levels are physiologically regulated, and hProCpepGFP is packaged and processed to CpepGFP that is co-stored in beta-secretory granules. Visualization of CpepGFP fluorescence provides a quantifiable measure of pancreatic islet insulin content that can be followed in live animals in states of health and disease. We examined loss of pancreatic insulin in hProCpepGFP transgenic mice mated to Akita mice that develop neonatal diabetes because of the expression of misfolded proinsulin. Loss of bystander insulin in Akita animals is detected initially as a block in CpepGFP/insulin production with intracellular accumulation of the precursor, followed ultimately by loss of pancreatic beta-cells. The data support that misfolded proinsulin perturbs bystander proinsulin in the endoplasmic reticulum, leading to beta-cell failure.
Assuntos
Diabetes Mellitus/congênito , Diabetes Mellitus/metabolismo , Proinsulina/química , Proinsulina/metabolismo , Dobramento de Proteína , Animais , Animais Recém-Nascidos , Efeito Espectador , Peptídeo C/metabolismo , Cruzamentos Genéticos , Diabetes Mellitus/patologia , Feminino , Fluorescência , Glucose/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Homeostase , Humanos , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Camundongos Transgênicos , Especificidade de Órgãos , Ratos , Via Secretória , Transgenes/genéticaRESUMO
A multitude of therapeutic agents have been available to treat patients with Type 2 diabetes. Unfortunately, many patients with advanced Type 2 diabetes continue to suffer from complications and premature death. To date, all available guidelines emphasize a variety of therapeutic aspects, goals, and pharmacological combinations, without directing the clinician as to which is a higher priority. The following review attempts to clarify which therapeutic option is more important for prognosis in patients with advanced type 2 diabetes. The body of evidence presented, reveal that the most important marker for prognosis is HbA1c. Each 1% incrementally higher HbA1c than ~7% is associated with 15%-45% reduced survival rates. Therefore, any agents that can achieve the time-sensitive objective of lowering HbA1c levels should be used.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas/análise , Hipoglicemiantes/uso terapêutico , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Hemoglobinas Glicadas/efeitos dos fármacos , Controle Glicêmico , Humanos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Prognóstico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Hypoxia-inducible factor-1alpha (HIF-1alpha) is a key regulator of the response to low oxygen levels and has been used for therapeutic angiogenesis. Various routes of administration have been used for delivering genes to the ischemic region including the intramuscular (IM) and intraarterial routes. When compared with these delivery methods, the intravenous (IV) route confers many advantages, including less invasiveness and lower cost. However, its use is hampered by the fact that it does not result in specific and robust tissue expression of the genes. Our aim was to determine the feasibility, safety, and therapeutic efficacy of systemic administration of adenoviral-mediated HIF-1alpha targeted to the endothelium. Using confocal microscopy and biodistribution studies we demonstrated that a modified murine preproendothelin-1 promoter (PPE1-3x) can target gene expression specifically to endothelial cells within ischemic muscle following systemic IV administration in C57BL/6 mice. Accordingly, an adenovirus expressing a PPE1-3x-regulated stabilized HIF-1alpha molecule, further activated by constitutive activation of its C-transactivation domain (C-TAD), was created. Systemic tail-vein administration of this adenovirus in a mouse hindlimb ischemia model resulted in enhanced blood perfusion, improved clinical outcome, and increased capillary density without systemic toxicity, in contrast to the profound systemic side effects and lack of therapeutic efficacy following cytomegalovirus (CMV)-regulated HIF-1alpha administration. Collectively, these data suggest that transcriptionally controlled systemic proangiogenic gene therapy is feasible, safe, and efficacious.
Assuntos
Terapia Genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isquemia/genética , Isquemia/terapia , Neovascularização Patológica/metabolismo , Adenoviridae/genética , Animais , Endotélio/metabolismo , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Isquemia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/genética , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , Especificidade por Substrato , Transgenes/genéticaRESUMO
Hypoxia-inducible factor-1α (HIF-1α) is a key regulator of the response to low oxygen levels and has been used for therapeutic angiogenesis. Various routes of administration have been used for delivering genes to the ischemic region including the intramuscular (IM) and intraarterial routes. When compared with these delivery methods, the intravenous (IV) route confers many advantages, including less invasiveness and lower cost. However, its use is hampered by the fact that it does not result in specific and robust tissue expression of the genes. Our aim was to determine the feasibility, safety, and therapeutic efficacy of systemic administration of adenoviral-mediated HIF-1α targeted to the endothelium. Using confocal microscopy and biodistribution studies we demonstrated that a modified murine preproendothelin-1 promoter (PPE1-3x) can target gene expression specifically to endothelial cells within ischemic muscle following systemic IV administration in C57BL/6 mice. Accordingly, an adenovirus expressing a PPE1-3x-regulated stabilized HIF-1α molecule, further activated by constitutive activation of its C-transactivation domain (C-TAD), was created. Systemic tail-vein administration of this adenovirus in a mouse hindlimb ischemia model resulted in enhanced blood perfusion, improved clinical outcome, and increased capillary density without systemic toxicity, in contrast to the profound systemic side effects and lack of therapeutic efficacy following cytomegalovirus (CMV)-regulated HIF-1α administration. Collectively, these data suggest that transcriptionally controlled systemic proangiogenic gene therapy is feasible, safe, and efficacious.
RESUMO
Despite improved surgical and radiotherapy techniques and the development of long-acting somatostatin analogs, some patients with acromegaly cannot attain biochemical remission. As a consequence they continue to endure debilitating symptoms and mortality remains high. Pegvisomant, a recombinant growth-hormone-receptor antagonist, suppresses production of insulin-like growth factor I. Since the introduction of this drug several years ago, long-term studies involving hundreds of patients have established efficacy of more than 85%. Raised transaminase concentrations have, however, been reported as a side effect of therapy, albeit an infrequent one. In addition, increases in tumor volume have been reported in several cases. In this Review we present the long-term data that have been gathered on pegvisomant therapy, discuss the related risks and benefits, and frame a potential therapeutic approach.
Assuntos
Acromegalia/tratamento farmacológico , Hormônio do Crescimento Humano/análogos & derivados , Receptores da Somatotropina/antagonistas & inibidores , Acromegalia/fisiopatologia , Osso e Ossos/metabolismo , Quimioterapia Combinada , Glucose/metabolismo , Coração/fisiopatologia , Hormônio do Crescimento Humano/efeitos adversos , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Lipídeos/sangue , Fígado/efeitos dos fármacos , Neoplasias Hipofisárias/induzido quimicamente , Neoplasias Hipofisárias/patologiaRESUMO
Background: In patients with type 2 diabetes, insulin therapy necessitates regular and frequent dosage titration to overcome variations in insulin requirements. The goal of this study was to evaluate changes in insulin requirements, using data from a technology-based insulin-titration service. Methods: To keep glycemia stable, the service adjusts and records insulin dosage at least weekly. Therefore, insulin dosage closely tracks insulin requirement. Events of considerable and persistent decrease in insulin requirements were identified by reductions in total daily dose (TDD) of insulin ≥25%. Periods ended when a persistent increase in TDD of insulin has started. The average frequency of hypoglycemia was expressed as any glucose reading <54 mg/dL (both inside or outside periods of decrease in insulin dosage) divided by the total number of months for each patient. Results: Patients (n = 246) were followed for 2.8 ± 0.9 years. Reductions of TDD of insulin were experienced by 70.3% of the patients, occurred 0.8 ± 0.5 times per year, lasted 10.0 ± 7.7 weeks, and insulin requirements declined by 39.9% ± 12.6%. The frequency of hypoglycemia (<54 mg/dL) was low, at 0.5 ± 0.6 per month, and the difference in frequencies in biphasic/premixed and basal-bolus insulin regimens was not statistically significant. Hypoglycemia was 6.5 times more prevalent during reductions in TDD of insulin. Conclusions: Sizeable changes in insulin requirements occur over time, which demand persistent and frequent titration to preserve treatment safety.
Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemia , Hipoglicemiantes , Insulina , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Fatores de TempoRESUMO
A major drawback of current approaches to antiangiogenic gene therapy is the lack of tissue-specific targeting. The aim of this work was to trigger endothelial cell-specific apoptosis, using adenoviral vector-mediated delivery of a chimeric death receptor derived from the modified endothelium-specific pre-proendothelin-1 (PPE-1) promoter. In the present study, we constructed an adenovirus-based vector that targets tumor angiogenesis. Transcriptional control was achieved by use of a modified endothelium-specific promoter. Expression of a chimeric death receptor, composed of Fas and TNF receptor 1, resulted in specific apoptosis of endothelial cells in vitro and sensitization of cells to the proapoptotic effect of TNF-alpha. The antitumoral activity of the vectors was assayed in two mouse models. In the model of B16 melanoma, a single systemic injection of virus to the tail vein caused growth retardation of tumor and reduction of tumor mass with central tumor necrosis. When the Lewis lung carcinoma lung-metastasis model was applied, i.v. injection of vector resulted in reduction of lung-metastasis mass, via an antiangiogenic mechanism. Moreover, by application of the PPE-1-based transcriptional control, a humoral immune response against the transgene was avoided. Collectively, these data provide evidence that transcriptionally controlled, angiogenesis-targeted gene therapy is feasible.
Assuntos
Terapia Genética , Neoplasias/terapia , Neovascularização Patológica/terapia , Transcrição Gênica , Receptor fas/genética , Adenoviridae , Animais , Apoptose/fisiologia , Bovinos , Células Endoteliais/metabolismo , Vetores Genéticos , Humanos , Fator de Necrose Tumoral alfa/metabolismo , Receptor fas/metabolismoRESUMO
AIMS: A third of the patients with Type 2 diabetes have an advance disease that requires complex pharmacotherapies and advanced expertise, dependent on multiple clinical interactions. Unfortunately, limited providers availability enables only sporadic interactions. Additionally, the expanding Accountable Care Organization (ACO) concept enhances providers' compensation when clinical performance is improving while limiting face-to-face clinic visits. METHODS: We developed an advanced type 2 specialty clinic model, geared toward frequent remote clinical interventions while limiting face-to-face clinic visits. The model was tested in a 1-year, prospective, randomized controlled clinical trial. N=60, patients were randomized 1:1, to the experimental or standard endocrinology clinics. RESULTS: Average A1c in the experimental arm decreased from 9.6±0.9% to 7.9±1.3%(p<0.0001). Whereas in the control it decreased from 8.9±0.8% to 8.6±1.9%(non-significant). More patients were treated with statins in the experimental arm compared to the control (93.3% vs. 66.7%; p=0.01). Face-to-face clinic visits occurred 1.5±0.7 times per year in the experimental arm compared to 3.6±4.0 in the control (p<0.0001). CONCLUSIONS: We believe that the presented model for a modified type 2 diabetes specialty clinic may enhance providers accessibility and patients' outcomes while improving reimbursement in the ACO model.
Assuntos
Organizações de Assistência Responsáveis/métodos , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 2/terapia , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controle , Modelagem Computacional Específica para o Paciente , Telemedicina/métodos , Terapia Combinada , Complicações do Diabetes/terapia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Correio Eletrônico , Feminino , Hemoglobinas Glicadas/análise , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Michigan , Pessoa de Meia-Idade , Ambulatório Hospitalar , Educação de Pacientes como Assunto , Relações Profissional-Paciente , TelefoneRESUMO
BACKGROUND: The role of incretin-based drugs in the treatment of patients with type 2 diabetes admitted to hospital has not been extensively assessed. In this study, we compared the safety and efficacy of a dipeptidyl peptidase-4 inhibitor (sitagliptin) plus basal insulin with a basal-bolus insulin regimen for the management of patients with type 2 diabetes in general medicine and surgery in hospitals. METHODS: We did a multicentre, prospective, open-label, non-inferiority randomised clinical trial (Sita-Hospital) in five hospitals in the USA, enrolling patients aged 18-80 years with type 2 diabetes and a random blood glucose concentration of 7·8-22·2 mmol/L who were being treated with diet or oral antidiabetic drugs or had a total daily insulin dose of 0·6 units per kg or less, admitted to general medicine and surgery services. We randomly assigned patients (1:1) to receive either sitagliptin plus basal glargine once daily (the sitagliptin-basal group) or a basal-bolus regimen with glargine once daily and rapid-acting insulin lispro or aspart before meals (the basal-bolus group) during the hospital stay. All other antidiabetic drugs were discontinued on admission. The randomisation was achieved by computer-generated tables with block stratification according to randomisation blood glucose concentrations (ie, higher or lower than 11·1 mmol/L). The primary endpoint of the trial was non-inferiority in mean differences between groups in their daily blood glucose concentrations during the first 10 days of therapy (point-of-care measurements; non-inferiority was deemed a difference <1 mmol/L). The safety endpoints included hypoglycaemia and uncontrolled hyperglycaemia leading to treatment failure. All participants who received at least one dose of study drug were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT01845831. FINDINGS: Between Aug 23, 2013, and July 27, 2015, we recruited 279 patients, and randomly assigned 277 to treatment; 138 to sitagliptin-basal and 139 to basal-bolus. The length of stay in hospital was similar for both groups (median 4 days [IQR 3-8] vs 4 [3-8] days, p=0·54). The mean daily blood glucose concentration in the sitagliptin-basal group (9·5 mmol/L [SD 2·7]) was not inferior to that in the basal-bolus group 9·4 mmol/L [2·7]) with a mean blood glucose difference of 0·1 mmol/L (95% CI -0·6 to 0·7). No deaths occurred in this trial. Treatment failure occurred in 22 patients (16%) in the sitagliptin-basal group versus 26 (19%) in the basal-bolus group (p=0·54). Hypoglycaemia occurred in 13 patients (9%) in the sitagliptin-basal group and in 17 (12%) in the basal-bolus group (p=0·45). No differences in hospital complications were noted between groups. Seven patients (5%) developed acute kidney injury in the sitagliptin-basal group and six (4%) in the basal-bolus group. One patient (0·7%) developed acute pancreatitis (in the basal-bolus group). INTERPRETATION: The trial met the non-inferiority threshold for the primary endpoint, because there was no significant difference between groups in mean daily blood glucose concentrations. Treatment with sitagliptin plus basal insulin is as effective and safe as, and a convenient alternative to, the labour-intensive basal-bolus insulin regimen for the management of hyperglycaemia in patients with type 2 diabetes admitted to general medicine and surgery services in hospital in the non-intensive-care setting. FUNDING: Merck.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gerenciamento Clínico , Hospitalização , Hipoglicemiantes/uso terapêutico , Fosfato de Sitagliptina/uso terapêutico , Idoso , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Medicina Geral/métodos , Hospitalização/tendências , Humanos , Hipoglicemiantes/farmacologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fosfato de Sitagliptina/farmacologia , Resultado do TratamentoRESUMO
Oxygenases are a family of enzymes that dioxygenate unsaturated fatty acids, thus initiating membrane oxidation and signaling molecule synthesis. The lipoxygenases (LOs), a family of lipid-peroxidizing enzymes that induce structural and metabolic changes in the cell in a number of pathophysiological conditions, belong to the oxygenases family. This class of enzymes has several subgroups, named 5-, 8-, 12- and 15-LOs, and these LO-isoforms are capable of oxygenating arachidonic and linoleic acid. 15-LOs were reported to play an inhibitory role in tumor angiogenesis and, consequently, they slow down carcinogenesis. It has been suggested that its anti-carcinogenic effect is conferred by promoting cell differentiation and apoptosis. Using transgenic mice that over-express 15-LO-1 in endothelial cells under the regulation of the murine preproendothelin-1 promoter, we studied its effect on tumor and metastasis growth. We found that 15-LO-1 inhibited tumor and metastasis growth in the transgenic mice in two different models of cancer (mammary gland and Lewis lung carcinoma). This inhibition was concomitant with a higher number of apoptotic cells in the metastases of the transgenic mice and with a complicated network of multiple small blood vessels. This finding targets 15-LO as a new candidate in the treatment of carcinogenesis.
Assuntos
Araquidonato 15-Lipoxigenase/fisiologia , Transformação Celular Neoplásica/genética , Endotelina-1/fisiologia , Neovascularização Patológica/genética , Animais , Apoptose/genética , Apoptose/fisiologia , Araquidonato 15-Lipoxigenase/biossíntese , Araquidonato 15-Lipoxigenase/genética , Vasos Sanguíneos , Carcinoma Pulmonar de Lewis/irrigação sanguínea , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Metástase Neoplásica/genética , Metástase Neoplásica/fisiopatologia , Regiões Promotoras Genéticas , Regulação para CimaRESUMO
Objective. To report the unusual case of an adrenal lymphangioma presenting in a patient with an adrenal cystic lesion and biochemical testing concerning for pheochromocytoma. The pertinent diagnostic and imaging features of adrenal lymphangiomas are reviewed. Methods. We describe a 59-year-old patient who presented with hyperhidrosis and a 2.2 by 2.2 cm left adrenal nodule. Biochemical evaluation revealed elevated plasma-free normetanephrine, urine normetanephrine, urine vanillylmandelic acid, and urine norepinephrine levels. Elevated plasma norepinephrine levels were not suppressed appropriately with clonidine administration. Results. Given persistent concern for pheochromocytoma, the patient underwent adrenalectomy. The final pathology was consistent with adrenal lymphangioma. Conclusions. Lymphangiomas are benign vascular lesions that can very rarely occur in the adrenal gland. Imaging findings are generally consistent with a cyst but are nonspecific. Excluding malignancy in patients presenting with adrenal cysts can be difficult. Despite its benign nature, the diagnosis of adrenal lymphangioma may ultimately require pathology.