RESUMO
Serious hypoglycemia is a major adverse event associated with insulin secretagogues. Previous studies have suggested a potential relationship between angiotensin-converting enzyme inhibitors (ACEIs) used with sulfonylureas and serious hypoglycemia, and widely used drug compendia warn of this potential drug-drug interaction. We investigated the association between serious hypoglycemia and concomitant use of ACEIs in patients receiving insulin secretagogues, using the self-controlled case series design and Medicaid claims data from 5 US states linked to Medicare claims from 1999-2011. The exposure of interest was active prescription for ACEIs during insulin secretagogue or metformin (negative control object drug) episodes. The outcome was hospital presentation for serious hypoglycemia, identified by discharge diagnosis codes in inpatient and emergency department claims (positive predictive value ~ 78-89%). We calculated confounder-adjusted rate ratios (RRs) and 95% confidence internals (CIs) of outcome occurrence during ACEI-exposed vs. ACEI-unexposed time using conditional Poisson regression. The RRs for ACEIs were not statistically elevated during observation time of glipizide (RR, 1.06; CI, 0.98-1.15), glyburide (RR, 1.05; CI, 0.96-1.15), repaglinide (RR, 1.15; CI, 0.94-1.41), or metformin (RR, 1.02; CI, 0.97-1.06); but was modestly elevated with glimepiride (RR, 1.23; CI, 1.11-1.37) and modestly reduced with nateglinide (RR, 0.73; CI, 0.56-0.96). The overall pattern of results do not suggest that ACEIs used with insulin secretagogues were associated with increased rates of serious hypoglycemia, with the possible exception of glimepiride.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Insulina/agonistas , Secretagogos/efeitos adversos , Demandas Administrativas em Assistência à Saúde , Idoso , Idoso de 80 Anos ou mais , Carbamatos/efeitos adversos , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Interações Medicamentosas , Feminino , Glipizida/efeitos adversos , Glibureto/efeitos adversos , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Medicaid , Metformina/efeitos adversos , Pessoa de Meia-Idade , Nateglinida/efeitos adversos , Farmacoepidemiologia , Piperidinas/efeitos adversos , Compostos de Sulfonilureia/efeitos adversos , Estados UnidosRESUMO
STUDY QUESTION: Are bisphenol A (BPA) and BPA analogs (BPA-A) safe for male human reproductive function? SUMMARY ANSWER: The endocrine function of human testes explants [assessed by measuring testosterone and insulin-like factor 3 (INSL3)] was impacted by exposure of the human adult testis explants to BPA/BPA-A. WHAT IS KNOWN ALREADY: The few epidemiologic studies performed suggest that bisphenols have potential endocrine disruptive properties, but they did not identify clear and direct patterns of endocrine disruption. STUDY DESIGN, SIZE, DURATION: Adult human testis explants in culture were exposed to BPA and the analogs bisphenol F (BPF), bisphenol S (BPS), bisphenol E (BPE), bisphenol B (BPB) and bisphenol A diglycidyl ether (BADGE) at 10-9-10-5 M for 24 or 48 h. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human adult testes were obtained from prostate cancer patients who had no hormone therapy, or from multiorgan donors. After ex vivo exposure to the investigated bisphenols, the measured outcomes were related to histopathology (gross morphology and germ cell viability determined by anti-caspase three immunohistochemistry), and the levels of testosterone, INSL3 and inhibin B were measured using immunoassays. The levels of mRNA encoding key enzymes of bisphenol biotransformation were investigated by quantitative PCR: UGT2B15 UDP (glucuronosyltransferase two family, polypeptide B15), GUSB (glucuronidase beta), SULT1A1 and 3 (sulfotransferase family 1 A member 1 and 3) and STS (steroid sulfatase). MAIN RESULTS AND THE ROLE OF CHANCE: A significant dose-dependent inhibition was found between testosterone levels measured in the culture medium and concentrations of BPA (P = 0.00778 at 24 h and P = 0.0291 at 48 h), BPE (P = 0.039) and BPF (P = 0.00663). The observed BPA and BPA-A-induced inhibition of testosterone production varied according to duration of exposure and BPA/BPA-A concentrations. BPA (10-9 M; P < 0.05), BPB (10-9 M; P < 0.05), BPS (10-9 and 10-8 M; P < 0.05) and BADGE (10-5 M; P < 0.05) increased Leydig cell INSL3 production. By contrast, BPE dose dependently inhibited INSL3 (P = 0.0372). Conversely, Sertoli cell function (inhibin B) and germ cell viability were not significantly affected by either bisphenols. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Environmental compounds cannot be deliberately administered to men, justifying the use of an ex vivo approach. A relatively low number of testes samples were available for analysis (n = 3, except for testosterone secretion with n = 5). The active concentrations of BPA and BPA-A used in the study were higher than those found in human biological fluids. WIDER IMPLICATIONS OF THE FINDINGS: Under our experimental conditions, direct exposure to BPA or BPA-A can result in endocrine disturbance in the adult human testis. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Inserm (Institut National de la Santé et de la Recherche Médicale), EHESP-School of Public Health, University of Rennes1, by grants from the Agence Nationale de la Recherche (ANR; grant#ANR-13-CESA-0012-03 NEWPLAST) and Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail (ANSES; grant#EST-2010/2/046 (BPATESTIS)). All authors declare they have no current or potential competing financial interests.
Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Insulina/agonistas , Drogas Antiandrogênicas não Esteroides/toxicidade , Fenóis/toxicidade , Proteínas/agonistas , Testículo/efeitos dos fármacos , Testosterona/antagonistas & inibidores , Adulto , Apoptose/efeitos dos fármacos , Arilsulfotransferase/genética , Arilsulfotransferase/metabolismo , Compostos Benzidrílicos/química , Disruptores Endócrinos/química , Compostos de Epóxi/toxicidade , Glucuronidase/genética , Glucuronidase/metabolismo , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Insulina/metabolismo , Células Intersticiais do Testículo/citologia , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Masculino , Drogas Antiandrogênicas não Esteroides/química , Fenóis/química , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Reprodutibilidade dos Testes , Células de Sertoli/citologia , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/metabolismo , Esteril-Sulfatase/genética , Esteril-Sulfatase/metabolismo , Sulfonas/toxicidade , Testículo/citologia , Testículo/metabolismo , Testosterona/metabolismo , Técnicas de Cultura de TecidosRESUMO
In our previous study, Atlantic salmon skin gelatin hydrolysed with flavourzyme possessed 42.5% dipeptidyl-peptidase (DPP)-IV inhibitory activity at a concentration of 5 mg mL(-1). The oral administration of the hydrolysate (FSGH) at a single dose of 300 mg per day in streptozotocin (STZ)-induced diabetic rats for 5 weeks was evaluated for its antidiabetic effect. During the 5-week experiment, body weight increased, and the food and water intake was reduced by FSGH in diabetic rats. The daily administration of FSGH for 5 weeks was effective for lowering the blood glucose levels of diabetic rats during an oral glucose tolerance test (OGTT). After the 5-week treatment, plasma DPP-IV activity was inhibited; the plasma activity of glucagon-like peptide-1 (GLP-1), insulin, and the insulin-to-glucagon ratio were increased by FSGH in diabetic rats. The results indicate that FSGH has the function of inhibiting GLP-1 degradation by DPP-IV, resulting in the enhancement of insulin secretion and improvement of glycemic control in STZ-induced diabetic rats.
Assuntos
Diabetes Mellitus Tipo 2/dietoterapia , Suplementos Nutricionais , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Proteínas de Peixes/uso terapêutico , Gelatina/uso terapêutico , Hidrolisados de Proteína/uso terapêutico , Salmo salar , Animais , Colúmbia Britânica , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Suplementos Nutricionais/economia , Dipeptidil Peptidase 4/sangue , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/economia , Inibidores da Dipeptidil Peptidase IV/isolamento & purificação , Inibidores da Dipeptidil Peptidase IV/metabolismo , Endopeptidases/metabolismo , Proteínas de Peixes/economia , Proteínas de Peixes/isolamento & purificação , Proteínas de Peixes/metabolismo , Indústria de Processamento de Alimentos/economia , Gelatina/economia , Gelatina/isolamento & purificação , Gelatina/metabolismo , Glucagon/antagonistas & inibidores , Glucagon/sangue , Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hiperglicemia/prevenção & controle , Resíduos Industriais/análise , Resíduos Industriais/economia , Insulina/agonistas , Insulina/sangue , Insulina/metabolismo , Secreção de Insulina , Masculino , Hidrolisados de Proteína/economia , Hidrolisados de Proteína/isolamento & purificação , Hidrolisados de Proteína/metabolismo , Ratos Sprague-Dawley , Pele/químicaRESUMO
Between 5 and 10% of the European population suffers from diabetes, and its prevalence is constantly rising, in Austria like in other countries. The main goals in the treatment of diabetes mellitus are the prevention of complications and organ damage, the prevention of severe hypo- and hyperglycaemia and the preservation of quality of life. Many patients with type 2 diabetes become insulin-dependent in the course of their disease. The application of a long acting insulin or insulin analogue is the simplest way of initiating an insulin therapy and is in accordance with current guidelines. Current scientific evidence shows that the use of long acting insulin analogues for type 2 diabetes; which can no longer be sufficiently controlled with oral antidiabetic agents, is simple, safe and efficacious. Thus, this treatment option should be available without any restrictions to physicians and patients in order to facilitate the beginning of an insulin regime. This position paper summarises up the current evidence concerning this subject.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/análogos & derivados , Áustria , Peso Corporal , Estudos de Coortes , Seguimentos , Humanos , Hipoglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/economia , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Insulina/agonistas , Insulina/economia , Insulina/uso terapêutico , Insulina Detemir , Insulina Glargina , Insulina de Ação Prolongada , Infarto do Miocárdio/epidemiologia , Guias de Prática Clínica como Assunto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Rosiglitazona , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/economia , Tiazolidinedionas/uso terapêuticoRESUMO
The purpose of this study was to compare in clinical and economic terms the long-acting insulin analogue detemir with intermediate-acting Neutral Protamine Hagedorn (NPH) insulin and with long-acting insulin glargine. Investigators used the validated Center for Outcomes Research (CORE) Diabetes Model to project clinical and cost outcomes over a 35-year base case time horizon; outcome data were extracted directly from randomized, controlled trials designed to compare detemir with NPH and with insulin glargine. Modeled patient characteristics were derived from corresponding trials, and simulations incorporated published quality-of-life utilities with cost data obtained from a Medicare perspective. Detemir, when compared with NPH, increased quality-adjusted life expectancy by 0.698 quality-adjusted life-years (QALYs). Lifetime direct medical costs were increased by 10,451 dollars per patient, although indirect costs were reduced by 4688 dollars. On the basis of direct costs, the cost per QALY gained with detemir was 14,974 dollars. In comparison with glargine, detemir increased quality-adjusted life expectancy by 0.063 QALYs, reduced direct medical costs by 2072 dollars per patient, and decreased indirect costs by 3103 dollars (dominant). Reductions in diabetes-related comorbidities were also associated with detemir in both instances, most notably in the complications of retinopathy and nephropathy. Relative reductions in rates of complications were greatest in the comparison of detemir with NPH. Results were most sensitive to variation in hemoglobin A1c (HbA1c) levels. However, variation among any of the key assumptions, including HbA1c, did not alter the relative results. Detemir represents an attractive clinical and economic intervention in the US health care setting compared with both NPH insulin and insulin glargine.