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1.
Diabetes Technol Ther ; 22(2): 66, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31971834
2.
Diabetes Obes Metab ; 22(3): 427-433, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31858718

RESUMO

AIM: To confirm the observed reduction in HbA1c for the 2.5 mg dose in EASE-3 by modelling and simulation analyses. MATERIALS AND METHODS: Independent of data from EASE-3 that tested 2.5 mg, we simulated the effect of a 2.5 mg dose through patient-level, exposure-response modelling in the EASE-2 clinical study. A primary semi-mechanistic model evaluated efficacy considering clinical insulin dose adjustments made after treatment initiation that potentially limited HbA1c reductions. The model was informed by pharmacokinetic, insulin dose, mean daily glucose and HbA1c data, and was verified by comparing the simulations with the observed HbA1c change in EASE-3. One of two empagliflozin phase 3 trials in type 1 diabetes (EASE-3 but not EASE-2) included a lower 2.5 mg dose. A placebo-corrected HbA1c reduction of 0.28% was demonstrated without the increased risk of diabetic ketoacidosis observed at higher doses (10 mg and 25 mg). Since only one trial included the lower dose, we aimed to confirm the observed reduction in HbA1c for the 2.5 mg dose by modelling and simulation analyses. RESULTS: The simulated 26-week mean HbA1c change was -0.41% without insulin dose adjustment and -0.29% at 26 weeks with insulin dose adjustment. A simplified (descriptive) model excluding insulin dose and mean daily glucose confirmed the -0.29% HbA1c change that would have been observed had the EASE-2 population received a 2.5 mg dose for 26/52 weeks. CONCLUSIONS: The HbA1c benefit of low-dose empagliflozin directly observed in the EASE-3 trial was confirmed by two modelling and simulation approaches.

5.
Diabetes Care ; 42(9): 1716-1723, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177179

RESUMO

OBJECTIVE: While sodium-glucose cotransporter inhibitor (SGLTi) therapy has been evaluated in type 1 diabetes (T1D) trials, patient reactions to benefits and risks are unknown. Using established methodology, we evaluated patient preferences for different adjunct-to-insulin therapy options in T1D. RESEARCH DESIGN AND METHODS: An online survey, completed by 701 respondents with T1D (231 U.S., 242 Canada, and 228 Germany), used conjoint analysis to present six hypothetical, masked, pairwise drug profile choices composed of different benefit-risk attributes and effect ranges. Data used in analyses were derived from actual phase 3 trials of a low-dose SGLTi (comparable to oral empagliflozin 2.5 mg q.d.), a high-dose SGLTi (comparable to oral sotagliflozin 400 mg q.d.), and an available adjunct-to-insulin therapy (comparable to subcutaneous pramlintide 60 µg t.i.d.). RESULTS: Conjoint analysis identified diabetic ketoacidosis risk as most important to patients (23% relative score; z test, P < 0.05); ranked second were HbA1c reduction (14%), risk of severe hypoglycemia (13%), oral versus injectable treatment (12%), and risk of genital infection (12%). Next was risk of nausea (11%), followed by weight reduction (8%) and the risk of diarrhea (7%). A low-dose SGLTi drug profile was identified by conjoint analysis as the top patient preference (83% of participants; z test, P < 0.05) versus high-dose SGLTi (8%) or pramlintide (9%). Separate from conjoint analysis, when respondents were asked to choose their preferred adjunct-to-insulin therapy (masked to drug name/dose), 69%, 17%, 6%, and 9% of respondents chose low-dose SGLTi, high-dose SGLTi, pramlintide, and insulin therapy alone, respectively. CONCLUSIONS: Low-dose SGLTi profile was the favored adjunct-to-insulin therapy by persons with T1D.

6.
N Engl J Med ; 381(7): 603-613, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31180194

RESUMO

BACKGROUND: Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed. METHODS: We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals. RESULTS: A total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization - 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed. CONCLUSIONS: Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Complexo CD3/antagonistas & inibidores , Diabetes Mellitus Tipo 1/prevenção & controle , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Criança , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Progressão da Doença , Método Duplo-Cego , Exantema/induzido quimicamente , Feminino , Teste de Tolerância a Glucose , Antígeno HLA-DR3 , Antígeno HLA-DR4 , Humanos , Contagem de Linfócitos , Linfopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Linfócitos T/imunologia , Adulto Jovem
7.
Diabetes ; 68(6): 1267-1276, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30967424

RESUMO

A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved ß-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test-stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved ß-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.


Assuntos
Soro Antilinfocitário/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Adolescente , Adulto , Peptídeo C/metabolismo , Relação CD4-CD8 , Criança , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Método Duplo-Cego , Feminino , Citometria de Fluxo , Hemoglobina A Glicada/metabolismo , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Masculino , Linfócitos T Reguladores/imunologia , Adulto Jovem
8.
Diabetes Care ; 42(6): 1147-1154, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30728224

RESUMO

Sodium-glucose cotransporter (SGLT) inhibitors are new oral antidiabetes medications shown to effectively reduce glycated hemoglobin (A1C) and glycemic variability, blood pressure, and body weight without intrinsic properties to cause hypoglycemia in people with type 1 diabetes. However, recent studies, particularly in individuals with type 1 diabetes, have demonstrated increases in the absolute risk of diabetic ketoacidosis (DKA). Some cases presented with near-normal blood glucose levels or mild hyperglycemia, complicating the recognition/diagnosis of DKA and potentially delaying treatment. Several SGLT inhibitors are currently under review by the U.S. Food and Drug Administration and European regulatory agencies as adjuncts to insulin therapy in people with type 1 diabetes. Strategies must be developed and disseminated to the medical community to mitigate the associated DKA risk. This Consensus Report reviews current data regarding SGLT inhibitor use and provides recommendations to enhance the safety of SGLT inhibitors in people with type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Cetoacidose Diabética , Inibidores do Transportador 2 de Sódio-Glicose , Consenso , Glucose , Humanos , Hipoglicemiantes , Gestão de Riscos , Sódio
9.
Diabetes Care ; 41(12): 2560-2569, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30287422

RESUMO

OBJECTIVE: To evaluate the safety and efficacy of empagliflozin 10- and 25-mg doses plus a unique lower dose (2.5 mg) as adjunct to intensified insulin in patients with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: The EASE (Empagliflozin as Adjunctive to inSulin thErapy) program (N = 1,707) included two double-blind, placebo-controlled phase 3 trials: EASE-2 with empagliflozin 10 mg (n = 243), 25 mg (n = 244), and placebo (n = 243), 52-week treatment; and EASE-3 with empagliflozin 2.5 mg (n = 241), 10 mg (n = 248), 25 mg (n = 245), and placebo (n = 241), 26-week treatment. Together they evaluated empagliflozin 10 mg and 25 mg, doses currently approved in treatment of type 2 diabetes, and additionally 2.5 mg on 26-week change in glycated hemoglobin (primary end point) and weight, glucose time-in-range (>70 to ≤180 mg/dL), insulin dose, blood pressure, and hypoglycemia. RESULTS: The observed largest mean placebo-subtracted glycated hemoglobin reductions were -0.28% (95% CI -0.42, -0.15) for 2.5 mg, -0.54% (-0.65, -0.42) for 10 mg, and -0.53% (-0.65, -0.42) for 25 mg (all P < 0.0001). Empagliflozin 2.5/10/25 mg doses, respectively, reduced mean weight by -1.8/-3.0/-3.4 kg (all P < 0.0001); increased glucose time-in-range by +1.0/+2.9/+3.1 h/day (P < 0.0001 for 10 and 25 mg); lowered total daily insulin dose by -6.4/-13.3/-12.7% (all P < 0.0001); and decreased systolic blood pressure by -2.1/-3.9/-3.7 mmHg (all P < 0.05). Genital infections occurred more frequently on empagliflozin. Adjudicated diabetic ketoacidosis occurred more with empagliflozin 10 mg (4.3%) and 25 mg (3.3%) but was comparable between empagliflozin 2.5 mg (0.8%) and placebo (1.2%). Severe hypoglycemia was rare and frequency was similar between empagliflozin and placebo. CONCLUSIONS: Empagliflozin improved glycemic control and weight in T1D without increasing hypoglycemia. Ketoacidosis rate was comparable between empagliflozin 2.5 mg and placebo but increased with 10 mg and 25 mg. Ketone monitoring for early ketoacidosis detection and intervention and lower empagliflozin doses may help to reduce this risk.


Assuntos
Compostos Benzidrílicos/administração & dosagem , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucosídeos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Adulto , Idoso , Compostos Benzidrílicos/efeitos adversos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Glucosídeos/efeitos adversos , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Placebos , Resultado do Tratamento , Perda de Peso
10.
Diabetes Care ; 41(9): 1917-1925, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30012675

RESUMO

OBJECTIVE: A pilot study suggested that combination therapy with low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that 1) low-dose ATG/GCSF or 2) low-dose ATG alone would slow the decline of ß-cell function in patients with new-onset T1D (duration <100 days). RESEARCH DESIGN AND METHODS: A three-arm, randomized, double-masked, placebo-controlled trial was performed by the Type 1 Diabetes TrialNet Study Group in 89 subjects: 29 subjects randomized to ATG (2.5 mg/kg intravenously) followed by pegylated GCSF (6 mg subcutaneously every 2 weeks for 6 doses), 29 to ATG alone (2.5 mg/kg), and 31 to placebo. The primary end point was mean area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test 1 year after initiation of therapy. Significance was defined as one-sided P value < 0.025. RESULTS: The 1-year mean AUC C-peptide was significantly higher in subjects treated with ATG (0.646 nmol/L) versus placebo (0.406 nmol/L) (P = 0.0003) but not in those treated with ATG/GCSF (0.528 nmol/L) versus placebo (P = 0.031). HbA1c was significantly reduced at 1 year in subjects treated with ATG and ATG/GCSF, P = 0.002 and 0.011, respectively. CONCLUSIONS: Low-dose ATG slowed decline of C-peptide and reduced HbA1c in new-onset T1D. Addition of GCSF did not enhance C-peptide preservation afforded by low-dose ATG. Future studies should be considered to determine whether low-dose ATG alone or in combination with other agents may prevent or delay the onset of the disease.


Assuntos
Soro Antilinfocitário/administração & dosagem , Citoproteção/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobina A Glicada/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Adolescente , Adulto , Soro Antilinfocitário/efeitos adversos , Peptídeo C/sangue , Criança , Diabetes Mellitus Tipo 1/fisiopatologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Células Secretoras de Insulina/fisiologia , Masculino , Projetos Piloto , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Adulto Jovem
12.
Physiol Behav ; 191: 123-130, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29655763

RESUMO

AIMS: Sleeping oxygen saturation (SaO2) and sleep stage duration have been linked with prediabetic alterations but the pathogenic pathways are not well understood. This study of insulin sensitive and resistant adults examined the effect on postprandial metabolic regulation of repeated mixed-meal challenges of different carbohydrate loading. The aim was to examine whether the relationship between lower sleeping oxygen saturation (SaO2) and poorer fasting and postprandial metabolic function may be linked with reduced slow wave sleep (SWS) and rapid eye movement (REM) duration, independent of age, sex and total adiposity. METHODS: The 24 men and women, aged 25-54 years, had no diabetes or other diagnosed conditions, were evaluated with polysomnography to derive indices of SaO2 and sleep architecture. In addition, an OGTT and two 14-h serial mixed-meal tests were administered over 3 successive in-patient days. The carbohydrate content of the mixed-meals was manipulated to compare a standard-load day with a double-load day (300 vs. 600 kcal/meal). Quantitative modeling was applied to derive ß-cell glucose sensitivity (ß-GS), early insulin secretion rate sensitivity (ESRS), and total postprandial insulinemia (AUCINS). RESULTS: Analyses showed that, for the 14-h tests, the SaO2 relationship with metabolic outcomes was associated significantly with percent time spent in REM but not SWS, independent of age, sex and total adiposity. Specifically, indirect pathways indicated that lower SaO2 was related to shorter REM duration, and shorter REM was respectively associated with higher ß-GS, ESRS, and AUCINS for the 300- and 600-load days (300 kcal/meal: ß = -8.68, p < .03, ß = -8.54, p < .002, and ß = -10.06, p < .008; 600 kcal/meal: ß = -11.45, p < .003, ß = -11.44, p < .001, and ß = -11.00, p < .03). CONCLUSION: Sleeping oxygen desaturation and diminished REM duration are associated with a metabolic pattern that reflects a compensatory adaptation of postprandial insulin metabolism accompanying preclinical diabetic risk.


Assuntos
Resistência à Insulina/fisiologia , Insulina/metabolismo , Oxigênio/sangue , Período Pós-Prandial/fisiologia , Sono/fisiologia , Adulto , Área Sob a Curva , Índice de Massa Corporal , Jejum , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia , Fases do Sono
15.
Pediatr Diabetes ; 19(3): 403-409, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29171129

RESUMO

BACKGROUND/OBJECTIVE: The extent of influence of BMI and age on C-peptide at the diagnosis of type 1 diabetes (T1D) is unknown. We thus studied the impact of body mass index Z-scores (BMIZ) and age on C-peptide measures at and soon after the diagnosis of T1D. METHODS: Data from Diabetes Prevention Trial-Type 1 (DPT-1) participants <18.0 years at diagnosis was analyzed. Analyses examined associations of C-peptide measures with BMIZ and age in 2 cohorts: oral glucose tolerance tests (OGTTs) at diagnosis (n = 99) and mixed meal tolerance tests (MMTTs) <6 months after diagnosis (n = 80). Multivariable linear regression was utilized. RESULTS: Fasting and area under the curve (AUC) C-peptide from OGTTs (n = 99) at diagnosis and MMTTs (n = 80) after diagnosis were positively associated with BMIZ and age (P < .001 for all). Associations persisted when BMIZ and age were included as independent variables in regression models (P < .001 for all). BMIZ and age explained 31%-47% of the variance of C-peptide measures. In an example, 2 individuals with identical AUC C-peptide values had an approximate 5-fold difference in values after adjustments for BMIZ and age. The association between fasting glucose and C-peptide decreased markedly when fasting C-peptide values were adjusted (r = 0.30, P < .01 to r = 0.07, n.s.). CONCLUSIONS: C-peptide measures are strongly and independently related to BMIZ and age at and soon after the diagnosis of T1D. Adjustments for BMIZ and age cause substantial changes in C-peptide values, and impact the association between glycemia and C-peptide. Such adjustments can improve assessments of ß-cell impairment at diagnosis.


Assuntos
Peptídeo C/sangue , Diabetes Mellitus Tipo 1/sangue , Adolescente , Fatores Etários , Índice de Massa Corporal , Criança , Diabetes Mellitus Tipo 1/diagnóstico , Feminino , Humanos , Masculino
16.
Diabetologia ; 61(1): 84-92, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28956083

RESUMO

AIMS/HYPOTHESIS: We aimed to examine: (1) whether specific glucose-response curve shapes during OGTTs are predictive of type 1 diabetes development; and (2) the extent to which the glucose-response curve is influenced by insulin secretion. METHODS: Autoantibody-positive relatives of people with type 1 diabetes whose baseline OGTT met the definition of a monophasic or biphasic glucose-response curve were followed for the development of type 1 diabetes (n = 2627). A monophasic curve was defined as an increase in OGTT glucose between 30 and 90 min followed by a decline of ≥ 0.25 mmol/l between 90 and 120 min. A biphasic response curve was defined as a decrease in glucose after an initial increase, followed by a second increase of ≥ 0.25 mmol/l. Associations of type 1 diabetes risk with glucose curve shapes were examined using cumulative incidence curve comparisons and proportional hazards regression. C-peptide responses were compared with and without adjustments for potential confounders. RESULTS: The majority of participants had a monophasic curve at baseline (n = 1732 [66%] vs n = 895 [34%]). The biphasic group had a lower cumulative incidence of type 1 diabetes (p < 0.001), which persisted after adjustments for age, sex, BMI z score and number of autoantibodies (p < 0.001). Among the monophasic group, the risk of type 1 diabetes was greater for those with a glucose peak at 90 min than for those with a peak at 30 min; the difference persisted after adjustments (p < 0.001). Compared with the biphasic group, the monophasic group had a lower early C-peptide (30-0 min) response, a lower C-peptide index (30-0 min C-peptide/30-0 min glucose), as well as a greater 2 h C-peptide level (p < 0.001 for all). CONCLUSIONS/INTERPRETATION: Those with biphasic glucose curves have a lower risk of progression to type 1 diabetes than those with monophasic curves, and the risk among the monophasic group is increased when the glucose peak occurs at 90 min than at 30 min. Differences in glucose curve shapes between the monophasic and biphasic groups appear to be related to C-peptide responses.


Assuntos
Peptídeo C/metabolismo , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/metabolismo , Teste de Tolerância a Glucose/métodos , Adulto , Glicemia/metabolismo , Feminino , Humanos , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade
17.
Diabetologia ; 61(3): 509-516, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29275427

RESUMO

Much progress has been made in type 1 diabetes research. Biological replacement of islet function has been achieved with pancreas transplantation and with islet transplantation. In the future, human embryonic stem cells and/or induced pluripotent stem cells may offer a potentially unlimited source of cells for islet replacement. Another potential strategy is to induce robust beta cell replication so that regeneration of islets can be achieved. Immune interventions are being studied with the hope of arresting the type 1 diabetes disease process to either prevent the disease or help preserve beta cell function. Mechanical replacement of islet cell function involves the use of glucose sensor-controlled insulin infusion systems. As all of these avenues are pursued, headlines often overstate the case, thus hyping any given advance, which provides enormous hope for patients and families seeking a cure for type 1 diabetes. Often, however, it is an animal study or a pilot trial that is being described. The reality is that translation to successful trials in human beings may not be readily achievable. This article discusses both the hype and the hopes in type 1 diabetes research.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/cirurgia , Animais , Humanos , Sistemas de Infusão de Insulina , Transplante das Ilhotas Pancreáticas , Transplante de Células-Tronco
18.
Diabetes Care ; 41(1): 14-31, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29263194

RESUMO

In December 2008, the U.S. Food and Drug Administration issued guidance to the pharmaceutical industry setting new expectations for the development of antidiabetes drugs for type 2 diabetes. This guidance expanded the scope and cost of research necessary for approval of such drugs by mandating long-term cardiovascular outcomes trials (CVOTs) for safety. Since 2008, 9 CVOTs have been reported, 13 are under way, and 4 have been terminated. Reassuringly, each of the completed trials demonstrated the noninferiority of their respective drugs to placebo for their primary cardiovascular (CV) composite end point. Notably, four additionally provided evidence of CV benefit in the form of significant decreases in the primary CV composite end point, two suggested reductions in CV death, and three suggested reductions in all-cause mortality. Although these trials have yielded much valuable information, whether that information justifies the investment of time and resources is controversial. In June 2016, a Diabetes Care Editors' Expert Forum convened to review the processes and challenges of CVOTs, discuss the benefits and limitations of their current designs, and weigh the merits of modifications that might improve the efficiency and clinical value of future trials. Discussion and analysis continued with the CVOT trial results released in June 2017 at the American Diabetes Association's Scientific Sessions and in September 2017 at the European Association for the Study of Diabetes scientific meeting. This article summarizes the discussion and findings to date.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Sistema Cardiovascular/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Idoso , Doenças Cardiovasculares/etiologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Diabetes Mellitus Tipo 2/complicações , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Determinação de Ponto Final , Feminino , Seguimentos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose , Resultado do Tratamento
19.
JAMA ; 318(19): 1891-1902, 2017 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-29164254

RESUMO

Importance: Type 1 diabetes requires major lifestyle changes and carries increased morbidity and mortality. Prevention or delay of diabetes would have major clinical effect. Objective: To determine whether oral insulin delays onset of type 1 diabetes in autoantibody-positive relatives of patients with type 1 diabetes. Design, Setting, and Participants: Between March 2, 2007, and December 21, 2015, relatives with at least 2 autoantibodies, including insulin autoantibodies and normal glucose tolerance, were enrolled in Canada, the United States, Australia, New Zealand, the United Kingdom, Italy, Sweden, Finland, and Germany. The main study group (n = 389) had first-phase insulin release on an intravenous glucose tolerance test that was higher than the threshold. The 55 patients in the secondary stratum 1 had an identical antibody profile as the main study group except they had first-phase insulin release that was lower than the threshold. Secondary strata 2 (n = 114) and strata 3 (n = 3) had different autoantibody profiles and first-phase insulin release threshold combinations. Follow-up continued through December 31, 2016. Interventions: Randomization to receive 7.5 mg/d of oral insulin (n = 283) or placebo (n = 277), including participants in the main study group who received oral insulin (n = 203) or placebo (n = 186). Main Outcome and Measures: The primary outcome was time to diabetes in the main study group. Significance was based on a 1-sided threshold of .05, and 1-sided 95% CIs are reported. Results: Of a total of 560 randomized participants (median enrollment age, 8.2 years; interquartile range [IQR], 5.7-12.1 years; 170 boys [60%]; 90.7% white non-Hispanic; 57.6% with a sibling with type 1 diabetes), 550 completed the trial including 389 participants (median age, 8.4 years; 245 boys [63%]), 382 (96%) in the main study group. During a median follow-up of 2.7 years (IQR, 1.5-4.6 years) in the main study group, diabetes was diagnosed in 58 participants (28.5%) in the oral insulin group and 62 (33%) in the placebo group. Time to diabetes was not significantly different between the 2 groups (hazard ratio [HR], 0.87; 95% CI, 0-1.2; P = .21). In secondary stratum 1 (n = 55), diabetes was diagnosed in 13 participants (48.1%) in the oral insulin group and in 19 participants (70.3%) in the placebo group. The time to diabetes was significantly longer with oral insulin (HR, 0.45; 95% CI, 0-0.82; P = .006). The HR for time to diabetes for the between-group comparisons for the 116 participants in the other secondary stratum was 1.03 (95% CI, 0-2.11; P = .53) and for the entire cohort of 560 participants was 0.83 (95% CI, 0-1.07; P = .11), which were not significantly different. The most common adverse event was infection (n = 254), with 134 events in the oral insulin group and 120 events in the placebo group, but no significant study-related adverse events occurred. Conclusions and Relevance: Among autoantibody-positive relatives of patients with type 1 diabetes, oral insulin at a dose of 7.5 mg/d, compared with placebo, did not delay or prevent the development of type 1 diabetes over 2.7 years. These findings do not support oral insulin as used in this study for diabetes prevention. Trial Registration: clinicaltrials.gov Identifier: NCT00419562.


Assuntos
Diabetes Mellitus Tipo 1/prevenção & controle , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Administração Oral , Adolescente , Autoanticorpos/sangue , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Família , Feminino , Seguimentos , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Insulina/imunologia , Masculino , Falha de Tratamento
20.
Diabetes Care ; 40(11): 1494-1499, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28860125

RESUMO

OBJECTIVE: We assessed dysglycemia and a T1D Diagnostic Index60 (Index60) ≥1.00 (on the basis of fasting C-peptide, 60-min glucose, and 60-min C-peptide levels) as prediagnostic end points for type 1 diabetes among Type 1 Diabetes TrialNet Pathway to Prevention Study participants. RESEARCH DESIGN AND METHODS: Two cohorts were analyzed: 1) baseline normoglycemic oral glucose tolerance tests (OGTTs) with an incident dysglycemic OGTT and 2) baseline Index60 <1.00 OGTTs with an incident Index60 ≥1.00 OGTT. Incident dysglycemic OGTTs were divided into those with (DYS/IND+) and without (DYS/IND-) concomitant Index60 ≥1.00. Incident Index60 ≥1.00 OGTTs were divided into those with (IND/DYS+) and without (IND/DYS-) concomitant dysglycemia. RESULTS: The cumulative incidence for type 1 diabetes was greater after IND/DYS- than after DYS/IND- (P < 0.01). Within the normoglycemic cohort, the cumulative incidence of type 1 diabetes was higher after DYS/IND+ than after DYS/IND- (P < 0.001), whereas within the Index60 <1.00 cohort, the cumulative incidence after IND/DYS+ and after IND/DYS- did not differ significantly. Among nonprogressors, type 1 diabetes risk at the last OGTT was greater for IND/DYS- than for DYS/IND- (P < 0.001). Hazard ratios (HRs) of DYS/IND- with age and 30- to 0-min C-peptide were positive (P < 0.001 for both), whereas HRs of type 1 diabetes with these variables were inverse (P < 0.001 for both). In contrast, HRs of IND/DYS- and type 1 diabetes with age and 30- to 0-min C-peptide were consistent (all inverse [P < 0.01 for all]). CONCLUSIONS: The findings suggest that incident dysglycemia without Index60 ≥1.00 is a suboptimal prediagnostic end point for type 1 diabetes. Measures that include both glucose and C-peptide levels, such as Index60 ≥1.00, appear better suited as prediagnostic end points.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Adolescente , Adulto , Peptídeo C/sangue , Criança , Pré-Escolar , Estudos de Coortes , Determinação de Ponto Final , Seguimentos , Teste de Tolerância a Glucose , Humanos , Lactente , Pessoa de Meia-Idade , Adulto Jovem
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