RESUMO
OBJECTIVE: To compare the long-term effects of glucose-lowering medications (insulin glargine U-100, glimepiride, liraglutide, and sitagliptin) when added to metformin on insulin sensitivity and ß-cell function. RESEARCH DESIGN AND METHODS: In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) cohort with type 2 diabetes (n = 4,801), HOMA2 was used to estimate insulin sensitivity (HOMA2-%S) and fasting ß-cell function (HOMA2-%B) at baseline and 1, 3, and 5 years on treatment. Oral glucose tolerance test ß-cell responses (C-peptide index [CPI] and total C-peptide response [incremental C-peptide/incremental glucose over 120 min]) were evaluated at the same time points. These responses adjusted for HOMA2-%S in regression analysis provided estimates of ß-cell function. RESULTS: HOMA2-%S increased from baseline to year 1 with glargine and remained stable thereafter, while it did not change from baseline in the other treatment groups. HOMA2-%B and C-peptide responses were increased to variable degrees at year 1 in all groups but then declined progressively over time. At year 5, CPI was similar between liraglutide and sitagliptin, and higher for both than for glargine and glimepiride [0.80, 0.87, 0.74, and 0.64 (nmol/L)/(mg/dL) * 100, respectively; P < 0.001], while the total C-peptide response was greatest with liraglutide, followed in descending order by sitagliptin, glargine, and glimepiride [1.54, 1.25, 1.02, and 0.87 (nmol/L)/(mg/dL) * 100, respectively, P < 0.001]. After adjustment for HOMA2-%S to obtain an estimate of ß-cell function, the nature of the change in ß-cell responses reflected those in ß-cell function. CONCLUSIONS: The differential long-term effects on insulin sensitivity and ß-cell function of four different glucose-lowering medications when added to metformin highlight the importance of the loss of ß-cell function in the progression of type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Metformina , Compostos de Sulfonilureia , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina Glargina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Glucose/uso terapêutico , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Resistência à Insulina/fisiologia , Peptídeo C , Glicemia , Metformina/uso terapêutico , Fosfato de Sitagliptina/uso terapêuticoRESUMO
OBJECTIVE: Canagliflozin, a sodium glucose cotransporter 2 inhibitor approved for the treatment of adults with type 2 diabetes (T2D), increases urinary glucose excretion (UGE) and lowers plasma glucose (PG) levels by reducing the renal threshold for glucose (RTG ). This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of canagliflozin in pediatric T2D patients. METHODS: Patients, aged 10 to 17 years with mean weight 107.2 kg and body mass index 38.2 kg/m2 , underwent PK and PD assessments after receiving a single daily dose of canagliflozin 100 mg (n = 8) or 300 mg (n = 9) for 14 days. Data are presented as mean (SD). RESULTS: There were dose-dependent increases in the PK of canagliflozin 100 and 300 mg, with maximum plasma concentrations and areas under plasma concentration curves that were similar to the corresponding values in adults. Mean 24-hour RTG fell to 84.6 (13.8) mg/dL with canagliflozin 100 mg and to 69.1 (9.6) mg/dL with canagliflozin 300 mg; also consistent with reductions in RTG in adults. Mean 24-hour UGE increased from 5.3 (10.5) g at baseline to 74.1 (37.4) g with canagliflozin 100 mg and from 0.1 (0.04) g to 68.6 (26.5) g with canagliflozin 300 mg. Both doses were well tolerated and the tablets had acceptable taste, smell, and swallowability. CONCLUSIONS: In pediatric T2D patients, canagliflozin 100 and 300 mg had PK and PD characteristics similar to those in adults with T2D, which is likely due to the relative maturity and increased body weight of youth affected with this disorder.
Assuntos
Canagliflozina/administração & dosagem , Canagliflozina/farmacocinética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Adolescente , Idade de Início , Brasil , Canagliflozina/efeitos adversos , Criança , Diabetes Mellitus Tipo 2/epidemiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Farmacocinética , Estados UnidosAssuntos
Diabetes Mellitus Tipo 1 , Glucagon , Adulto , Glicemia , Humanos , Hipoglicemia , InsulinaRESUMO
Type 2 diabetes is a significant and increasing burden in adolescents and young adults. Clear strategies for research, prevention, and treatment of the disease in these vulnerable patients are needed. Evidence suggests that type 2 diabetes in children is different not only from type 1 but also from type 2 diabetes in adults. Understanding the unique pathophysiology of type 2 diabetes in youth, as well as the risk of complications and the psychosocial impact, will enable industry, academia, funding agencies, advocacy groups, and regulators to collectively evaluate both current and future research, treatment, and prevention approaches. This Consensus Report characterizes type 2 diabetes in children, evaluates the fundamental differences between childhood and adult disease, describes the current therapeutic options, and discusses challenges to and approaches for developing new treatments.
Assuntos
Atenção à Saúde , Complicações do Diabetes/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Adolescente , Idade de Início , Alostase , Criança , Consenso , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/psicologia , Diabetes Mellitus Tipo 2/terapia , Dietoterapia , Gerenciamento Clínico , Etnicidade/estatística & dados numéricos , Terapia por Exercício , Humanos , Hipoglicemiantes/uso terapêutico , Grupos Minoritários/estatística & dados numéricos , Risco , Comportamento de Redução do Risco , Fatores Socioeconômicos , Estados Unidos/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: Treatment of severe hypoglycemia with loss of consciousness or seizure outside of the hospital setting is presently limited to intramuscular glucagon requiring reconstitution immediately prior to injection, a process prone to error or omission. A needle-free intranasal glucagon preparation was compared with intramuscular glucagon for treatment of insulin-induced hypoglycemia. RESEARCH DESIGN AND METHODS: At eight clinical centers, a randomized crossover noninferiority trial was conducted involving 75 adults with type 1 diabetes (mean age, 33 ± 12 years; median diabetes duration, 18 years) to compare intranasal (3 mg) versus intramuscular (1 mg) glucagon for treatment of hypoglycemia induced by intravenous insulin. Success was defined as an increase in plasma glucose to ≥70 mg/dL or ≥20 mg/dL from the glucose nadir within 30 min after receiving glucagon. RESULTS: Mean plasma glucose at time of glucagon administration was 48 ± 8 and 49 ± 8 mg/dL at the intranasal and intramuscular visits, respectively. Success criteria were met at all but one intranasal visit and at all intramuscular visits (98.7% vs. 100%; difference 1.3%, upper end of 1-sided 97.5% CI 4.0%). Mean time to success was 16 min for intranasal and 13 min for intramuscular (P < 0.001). Head/facial discomfort was reported during 25% of intranasal and 9% of intramuscular dosing visits; nausea (with or without vomiting) occurred with 35% and 38% of visits, respectively. CONCLUSIONS: Intranasal glucagon was highly effective in treating insulin-induced hypoglycemia in adults with type 1 diabetes. Although the trial was conducted in a controlled setting, the results are applicable to real-world management of severe hypoglycemia, which occurs owing to excessive therapeutic insulin relative to the impaired or absent endogenous glucagon response.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucagon/administração & dosagem , Hormônios/uso terapêutico , Administração Intranasal , Adulto , Glicemia/efeitos dos fármacos , Estudos Cross-Over , Diabetes Mellitus Tipo 1/sangue , Feminino , Humanos , Hipoglicemia/induzido quimicamente , Insulina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE: To examine the current extent of the obesity problem in 2 large pediatric clinical registries in the US and Europe and to examine the hypotheses that increased body mass index (BMI) z-scores (BMIz) are associated with greater hemoglobin A1c (HbA1c) and increased frequency of severe hypoglycemia in youth with type 1 diabetes (T1D). STUDY DESIGN: International (World Health Organization) and national (Centers for Disease Control and Prevention/German Health Interview and Examination Survey for Children and Adolescents) BMI references were used to calculate BMIz in participants (age 2-<18 years and ≥ 1 year duration of T1D) enrolled in the T1D Exchange (n = 11,435) and the Diabetes Prospective Follow-up (n = 21,501). Associations between BMIz and HbA1c and severe hypoglycemia were assessed. RESULTS: Participants in both registries had median BMI values that were greater than international and their respective national reference values. BMIz was significantly greater in the T1D Exchange vs the Diabetes Prospective Follow-up (P < .001). After stratification by age-group, no differences in BMI between registries existed for children 2-5 years, but differences were confirmed for 6- to 9-, 10- to 13-, and 14- to 17-year age groups (all P < .001). Greater BMIz were significantly related to greater HbA1c levels and more frequent occurrence of severe hypoglycemia across the registries, although these associations may not be clinically relevant. CONCLUSIONS: Excessive weight is a common problem in children with T1D in Germany and Austria and, especially, in the US. Our data suggest that obesity contributes to the challenges in achieving optimal glycemic control in children and adolescents with T1D.
Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Obesidade/epidemiologia , Adolescente , Áustria/epidemiologia , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Alemanha/epidemiologia , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemia/epidemiologia , Masculino , Sistema de Registros , Estados Unidos/epidemiologiaRESUMO
OBJECTIVES: To describe changes in weight and body mass index (BMI) during the first year following diagnosis of type 1 diabetes (T1D) and associations with demographic and clinical characteristics. STUDY DESIGN: The Pediatric Diabetes Consortium includes 7 US centers with prospective longitudinal data from initial T1D diagnosis. This analysis includes 530 youth with diabetes duration of ≥1 year and measures of BMI at 3 and 12 months after diagnosis. BMI trajectory of participants and relationships between the change in BMI z-score from baseline (3 months) to 12 months with demographic characteristics, hemoglobin A1c at baseline, and insulin delivery mode at baseline were evaluated. RESULTS: As a group, BMI z-scores increased sharply from diagnosis for 1-3 months but remained relatively stable from +0.51 at 3 months to +0.48 at 12 months. Children aged 2-<5 years experienced a significant positive change in BMI z-score between 3 and 12 months, and there was a similar trend among girls that did not reach statistical significance. No significant differences were found for race, socioeconomic status, or insulin delivery mode. CONCLUSIONS: These data suggest that increased BMI during the first year of treatment of most youth with T1D reflects regain of weight lost before diagnosis. There is, however, a propensity toward additional weight gain in younger children and girls.
Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Adolescente , Índice de Massa Corporal , Peso Corporal , Criança , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Insulina/administração & dosagem , Estudos Longitudinais , Masculino , Estudos Prospectivos , Aumento de PesoRESUMO
OBJECTIVES: To describe the body mass index (BMI) distribution of children developing autoimmune type 1 diabetes (T1D) compared with the general population and to assess factors associated with BMI at T1D onset. STUDY DESIGN: Children age 2-<19 years enrolled in the Pediatric Diabetes Consortium at 7 US pediatric diabetes centers at T1D onset were included. Eligibility for analysis required a diagnosis of T1D, ≥1 positive diabetes autoantibody, and availability of BMI within 14 days of diagnosis. BMI at diagnosis was compared with the general population as described by the 2000 Centers for Disease Control. Regression analysis was used to assess the association between BMI and various participant characteristics. RESULTS: BMI scores for the 490 participants were slightly lower than the 2000 Centers for Disease Control population (P = .04). The median BMI percentile for age and sex was 48(th), 11% of the children were overweight (BMI ≥85(th) and <95(th) percentile), 8% obese (BMI ≥95(th) and <99(th) percentile), and 2% severely obese (≥99(th) percentile), percentages that were comparable across age and sex groups. Higher BMI Z-scores were associated with African American and Hispanic race/ethnicity (P = .001) and lower hemoglobin A1c (P < .001), and diabetic ketoacidosis, age, and Tanner stage were not associated. CONCLUSIONS: Although the BMI distribution in children developing autoimmune T1D was lower than that of the general population, 21% of children were obese or overweight. Youth who are overweight, obese, racial/ethnic minority, and/or present without diabetic ketoacidosis should not be presumed to have type 2 diabetes because many patients with autoantibody-positive T1D present with the same clinical characteristics.
Assuntos
Índice de Massa Corporal , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/fisiopatologia , Adolescente , Fatores Etários , Autoimunidade , Composição Corporal , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Modelos Estatísticos , Análise Multivariada , Obesidade/complicações , Sobrepeso , Fatores SexuaisRESUMO
OBJECTIVE: To define the demographic and clinical characteristics of children at the onset of type 1 diabetes (T1D), with particular attention to the frequency of diabetic ketoacidosis (DKA). STUDY DESIGN: The Pediatric Diabetes Consortium enrolled children with new-onset T1D into a common database. For this report, eligible subjects were aged <19 years, had a pH or HCO(3) value recorded at diagnosis, and were positive for at least one diabetes-associated autoantibody. Of the 1054 children enrolled, 805 met the inclusion criteria. A pH of <7.3 and/or HCO(3) value of <15 mEq/L defined DKA. Data collected included height, weight, hemoglobin A1c, and demographic information (eg, race/ethnicity, health insurance status, parental education, family income). RESULTS: The 805 children had a mean age of 9.2 years, 50% were female; 63% were non-Hispanic Caucasian. Overall, 34% of the children presented in DKA, half with moderate or severe DKA (pH <7.2). The risk for DKA was estimated as 54% in children aged <3 years and 33% in those aged ≥ 3 years (P = .006). In multivariate analysis, younger age (P = .002), lack of private health insurance (P < .001), African-American race (P = .01), and no family history of T1D (P = .001) were independently predictive of DKA. The mean initial hemoglobin A1c was higher in the children with DKA compared with those without DKA (12.5% ± 1.9% vs 11.1% ± 2.4%; P < .001). CONCLUSION: The incidence of DKA in children at the onset of T1D remains high, with approximately one-third presenting with DKA and one-sixth with moderate or severe DKA. Increased awareness of T1D in the medical and lay communities is needed to decrease the incidence of this life-threatening complication.
Assuntos
Diabetes Mellitus Tipo 1/complicações , Cetoacidose Diabética/etiologia , Criança , Cetoacidose Diabética/epidemiologia , Feminino , Humanos , Incidência , Masculino , Estudos ProspectivosRESUMO
OBJECTIVES: To compare long-acting insulin glargine (Lantus) with intermediate-acting insulin (neutral protamine Hagedorn [NPH]/Lente) when used as the basal component of a multiple daily injection (MDI) regimen with prandial insulin lispro (Humalog) in adolescents with type 1 diabetes mellitus (T1DM). STUDY DESIGN: This was an active-controlled, randomized, open-label, sex-stratified, 2-arm, parallel-group comparison of once-daily insulin glargine with twice-daily NPH/Lente in an MDI regimen. Changes in glycated hemoglobin A1C (A1C), occurrence of hypoglycemia, and adverse events were assessed in 175 patients (age 9 to 17 years) with T1DM. RESULTS: The overall mean change in A1C from baseline to week 24 was similar in the 2 groups: insulin glargine (n = 76), -0.25% +/- 0.14%; NPH/Lente (n = 81), 0.05% +/- 0.13% (P = .1725). However, an analysis of covariance, adjusting for baseline A1C, revealed a strong study arm effect on the slopes of the regression lines, indicating that the reduction in A1C was significantly greater with insulin glargine in those patients with higher baseline A1C values. The rate of confirmed glucose values <70 mg/dL was higher in the patients receiving insulin glargine (P = .0298). No differences in the rate of severe hypoglycemia (P = .1814) or the occurrence of glucose levels <50 mg/dL (P = .82) or <36 mg/dL (P = .32) were found between the 2 groups. CONCLUSIONS: Insulin glargine is well tolerated in MDI regimens for pediatric patients with T1DM and may be more efficacious than NPH/Lente in those with elevated A1C.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina Isófana/administração & dosagem , Insulina/análogos & derivados , Adolescente , Índice de Massa Corporal , Criança , Diabetes Mellitus Tipo 1/sangue , Feminino , Hemoglobinas Glicadas/análise , Humanos , Insulina/administração & dosagem , Insulina Glargina , Insulina de Ação Prolongada , MasculinoRESUMO
OBJECTIVE: To examine the feasibility of daily use of a continuous glucose monitor, the FreeStyle Navigator Continuous Glucose Monitoring System ("Navigator"), in children with type 1 diabetes (T1D). STUDY DESIGN: After a masked Navigator was used for 4 to 7 days to establish a baseline level of glycemic control, 30 insulin pump users with T1D (average age 11.2 years) were asked to use the Navigator daily for 13 weeks. RESULTS: Subjects averaged 149 h/wk of Navigator use during the first 4 weeks, which decreased slightly to 134 h/wk during weeks 9 to 13 (P = .006). Mean hemoglobin A1c improved from 7.1% at baseline to 6.8% at 13 weeks (P = .02), and the percentage of glucose values between 71 and 180 mg/dL increased from 52% to 60% (P = .01). Subjects and parents reported high satisfaction with the Navigator on the Continuous Glucose Monitor Satisfaction Scale. Two subjects had severe skin reactions related to sensor mount adhesive. CONCLUSION: This study indicates that incorporating real-time continuous glucose monitoring into the daily treatment of children with T1D is feasible. The results provide a compelling rationale for conducting a randomized trial of daily use of a continuous glucose monitor in children with T1D.
Assuntos
Automonitorização da Glicemia , Diabetes Mellitus Tipo 1/sangue , Monitorização Ambulatorial , Adolescente , Automonitorização da Glicemia/efeitos adversos , Automonitorização da Glicemia/instrumentação , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/terapia , Estudos de Viabilidade , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Sistemas de Infusão de Insulina , Masculino , Monitorização Ambulatorial/efeitos adversos , Monitorização Ambulatorial/instrumentação , Satisfação do Paciente , Projetos PilotoRESUMO
OBJECTIVE: To investigate the impact of factors that might interfere with optimal glycemic control in youth with type 1 diabetes mellitus (T1DM) in the current era of intensive management, including the interplay of race/ethnicity and socioeconomic status (SES) on HbA1c levels. STUDY DESIGN: This study comprised a database review of all patients under age 18 years with T1DM for at least 6 months duration. Sex, age, race/ethnicity, duration of diabetes, mode of insulin administration (pump vs injection), body mass index, SES, and HbA1c level were recorded at each patient's most recent visit between January and September 2003. RESULTS: Mean HbA1c level for the 455 patients was 7.6% +/- 1.4%; only 31% of patients failed to meet the therapeutic goal of < 8.0%. Multiple linear regression analysis identified female sex (P = .02), older age (P = .001), longer duration of diabetes (P < .001), injection therapy (P < .001), and lower SES (P = .001) as significantly associated with higher HbA1c level. After adjustment for SES, race/ethnicity was not a determinant of HbA1c level. CONCLUSIONS: Low SES had a greater association with poor metabolic control than did race/ethnicity, which was not associated with differences in HbA1c level after controlling for SES. Most children were able to attain glycemic targets at least as good as the Diabetes Control and Complications Trial recommendations in a large clinical practice.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Criança , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/etnologia , Etnicidade/estatística & dados numéricos , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Injeções Subcutâneas , Sistemas de Infusão de Insulina , Masculino , Fatores Socioeconômicos , Resultado do TratamentoRESUMO
OBJECTIVE: To examine the effect of exercise on overnight hypoglycemia in children with type 1 diabetes mellitus (T1DM). STUDY DESIGN: At 5 clinical sites, 50 subjects with T1DM (age 11 to 17 years) were studied in a clinical research center on 2 separate days. One day included an afternoon exercise session on a treadmill. On both days, frequently sampled blood glucose levels were measured at the DirecNet central laboratory. Insulin doses were similar on both days. RESULTS: During exercise, plasma glucose levels fell in almost all subjects; 11 (22%) developed hypoglycemia. Mean glucose level from 10 pm to 6 am was lower on the exercise day than on the sedentary day (131 vs 154 mg/dL; P=.003). Hypoglycemia developed overnight more often on the exercise nights than on the sedentary nights (P=.009), occurring on the exercise night only in 13 (26%), on the sedentary night only in 3 (6%), on both nights in 11 (22%), and on neither night in 23 (46%). Hypoglycemia was unusual on the sedentary night if the pre-bedtime snack glucose level was>130 mg/dL. CONCLUSIONS: These findings indicate that overnight hypoglycemia after exercise is common in children with T1DM and support the importance of modifying diabetes management after afternoon exercise to reduce the risk of hypoglycemia.
Assuntos
Glicemia/metabolismo , Ritmo Circadiano/fisiologia , Diabetes Mellitus Tipo 1/sangue , Exercício Físico/fisiologia , Hipoglicemia/etiologia , Adolescente , Criança , Estudos de Coortes , Estudos Cross-Over , Diabetes Mellitus Tipo 1/complicações , Feminino , Humanos , MasculinoRESUMO
OBJECTIVE: The workup of hypoglycemia requires frequent glucose sampling. We designed these studies to determine if the Continuous Glucose Monitoring System (CGMS) and the GlucoWatch G2 Biographer (GW2B) are sufficiently accurate to use in nondiabetic children. Study design Fifteen healthy children (aged 9-17 years, 11 boys) wore a GW2B and a CGMS during a 24-hour period, and reference serum glucose was measured hourly during the day and half-hourly overnight. RESULTS: Compared with the reference glucose, the median absolute difference in concentrations measured by the GW2B (487 pairs) was 13 mg/dL, and the difference measured by the CGMS was 17 mg/dL (668 pairs), with 30% and 42% of values using the GW2B and CGMS, respectively, deviating >20 mg/dL from the reference value. The GW2B reported values <60 mg/dL in 73% of subjects, the CGMS in 60% of subjects. In none of these episodes was serum glucose truly low. Spurious high glucose concentrations also were observed with the sensors. The mean reference glucose was lowest at 5 am (89 mg/dL) and highest at 11:30 pm (106 mg/dL) during the 24-hour period. CONCLUSIONS: Neither the CGMS nor the GW2B is accurate enough to establish population standards of the glycemic profile of healthy children and cannot be recommended in the workup of hypoglycemia in nondiabetic youth.