Clinical trials in youth with type 2 diabetes.
Ontology highlight
ABSTRACT:
SUBMITTER: Gemmill JA
PROVIDER: S-EPMC3405735 | biostudies-other | 2011 Feb
REPOSITORIES: biostudies-other
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Clinical trials in youth with type 2 diabetes.
Gemmill Julie Anne L JA Brown Rebecca J RJ Nandagopal Radha R Rodriguez Luisa M LM Rother Kristina I KI
Pediatric diabetes 20110201 1
Type 2 diabetes in youth was almost unheard of only two decades ago. However, tracking the recent dramatic rise in childhood obesity, type 2 diabetes has become increasingly prevalent. Thus, there is an urgent need for high-quality clinical trials to increase in-depth knowledge about pathophysiology, optimal treatment, and prevention. We therefore systematically reviewed published and ongoing clinical trials of type 2 diabetes in children and adolescents. The results demonstrate that (i) few ran ...[more]
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Project description:PURPOSE:To better understand and overcome difficulties with recruitment of adolescents with type 2 diabetes into clinical trials at three United States institutions, we reviewed recruitment and retention strategies in clinical trials of youth with various chronic conditions. We explored whether similar strategies might be applicable to pediatric patients with type 2 diabetes. METHODS:We compiled data on recruitment and retention of adolescents with type 2 diabetes at three centers (National Institutes of Health, Bethesda, Maryland; Baylor College of Medicine, Houston, Texas; and Children's National Medical Center, Washington, DC) from January 2009 to December 2011. We also conducted a thorough literature review on recruitment and retention in adolescents with chronic health conditions. RESULTS:The number of recruited patients was inadequate for timely completion of ongoing trials. Our review of recruitment strategies in adolescents included monetary and material incentives, technology-based advertising, word-of-mouth referral, and continuous patient-research team contact. Cellular or Internet technology appeared promising in improving participation among youths in studies of various chronic conditions and social behaviors. CONCLUSIONS:Adolescents with type 2 diabetes are particularly difficult to engage in clinical trials. Monetary incentives and use of technology do not represent "magic bullets," but may presently be the most effective tools. Future studies should be conducted to explore motivation in this population. We speculate that (1) recruitment into interventional trials that address the main concerns of the affected youth (e.g., weight loss, body image, and stress management) combined with less tangible outcomes (e.g., blood glucose control) may be more successful; and (2) study participation and retention may be improved by accommodating patients' and caregivers' schedules, by scheduling study visits before and after working hours, and in more convenient locations than in medical facilities.
| S-EPMC4163943 | biostudies-literature
Project description:During the past one to two decades, substantial progress has been made in our understanding of the immunopathology of type 1 diabetes (T1D) and the potential for immune interventions that can alter the natural history of the disease. This progress has resulted from the use of standardized study designs, endpoints, and, to a certain extent, mechanistic analyses in intervention trials in the setting of new-onset T1D. To date, most of these trials have involved single-agent interventions but, increasingly, future trials will test therapeutic combinations that are based on a compelling scientific rationale and testable mechanistic hypotheses. These increasingly complex trials will benefit from novel trial designs (such as factorial or adaptive designs), enhanced clinical endpoints that more directly assess islet pathology (such as β-cell death assays and islet or pancreatic imaging), improved responder analyses, and sophisticated mechanistic assays that provide deep phenotyping of lymphocyte subsets, gene expression profiling, in vitro T cell functional assessments, and antigen-specific responses. With this developing armamentarium of enhanced trial designs, endpoints, and clinical and mechanistic response analyses, we can expect substantial progress in better understanding the breakdown in immunologic tolerance in T1D and how to restore it to achieve significant and long-lasting preservation of islet function.
| S-EPMC4903883 | biostudies-literature
Project description:IntroductionIn recent decades, the dramatic rise of obesity among youth in the US has been accompanied by a rise in the prevalence of type 2 diabetes (T2D) in this population. This alarming trend underscores the importance of conducting trials to evaluate new therapies in children with T2D.MethodsA targeted review of peer-reviewed literature and trials registered on www.clinicaltrials.gov was conducted in January 2021 to identify pharmaceutical interventional studies in youth with T2D. Information regarding enrollment data, study design elements, subjects' baseline characteristics, and key treatment outcomes was documented.ResultsAmong the 16 clinical studies included in this review, only five appeared to meet projected enrollment targets in < 4 years. Although three other studies met recruitment targets, two took approximately 5 years to complete and the third took nearly 10 years.ConclusionsDespite legislation requiring evaluation of pharmaceutical treatments in pediatric populations, surprisingly few interventional studies have been conducted in children with T2D. This review highlights that recruitment challenges may be impeding the conduct and completion of interventional studies. Consequently, few pharmaceutical treatments have been proven to be effective and approved for children with T2D. Metformin and liraglutide remain the only non-insulin treatments formally approved in the US for use in this population. More clinical research is needed to support regulatory decision-making as well as treatment decisions for children with T2D in clinical settings. Sponsors and investigators will need to implement strategies for improving trial enrollment as well as work with regulatory agencies to develop novel study designs that may require fewer patients.
| S-EPMC8519987 | biostudies-literature
Project description:The incidence of type 2 diabetes in children and adolescents in the United States rose at an annual rate of 4.8% between 2002-2003 and 2014-2015. Type 2 diabetes progresses more aggressively to complications than type 1 diabetes. For example, in one large epidemiological study, proliferative retinopathy affected 5.6% and 9.1% of children with type 1 and type 2 diabetes, respectively. Screening begins at age 10 or at onset of puberty, and is recommended among children with a BMI% ≥85 with risk factors such as a family history and belonging to a high risk racial or ethnic or racial group. HbA1C% is preferred for screening as it does not require fasting. As distinguishing between type 1 and type 2 diabetes is not straightforward, all children with new onset disease should undergo autoantibody testing. Results of lifestyle interventions for control of type 2 diabetes have been disappointing, but are still recommended for their educational value and the potential impact upon some participants. There is limited evidence for the benefit of newer mediations. Liraglutide, a GLP-1 agonist, however, has been shown to significantly reduce HbA1C% in one study and is now approved for children. Liraglutide should be considered as second line therapy.
| S-EPMC8126957 | biostudies-literature
Project description:BackgroundYouth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Endothelial function magnetic resonance imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using endothelial function magnetic resonance imaging, we evaluated peripheral and coronary artery structure and endothelial function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers. We isolated and characterized plasma-derived small extracellular vesicles and evaluated their effects on inflammatory and signaling biomarkers in healthy human coronary artery endothelial cells to validate the imaging findings.MethodsRight coronary wall thickness, coronary artery flow-mediated dilation, and brachial artery flow-mediated dilation were measured at baseline and during isometric handgrip exercise using a 3.0T magnetic resonance imaging. Human coronary artery endothelial cells were treated with Y-T2D plasma-derived small extracellular vesicles. Protein expression was measured by Western blot analysis, oxidative stress was measured using the redox-sensitive probe dihydroethidium, and nitric oxide levels were measured by 4-amino-5-methylamino-2',7'-difluororescein diacetate.ResultsY-T2D (n=20) had higher hemoglobin A1c and high-sensitivity C-reactive protein, but similar total and LDL (low-density lipoprotein)-cholesterol compared with healthy peers (n=16). Y-T2D had greater coronary wall thickness (1.33±0.13 versus 1.22±0.13 mm; P=0.04) and impaired endothelial function: lower coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; P<0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; P=0.001). Y-T2D plasma-derived small extracellular vesicles reduced phosphorylated endothelial nitric oxide synthase expression and nitric oxide levels, increased reactive oxygen species production, and elevated ICAM (intercellular adhesion molecule)-mediated inflammatory pathways in human coronary artery endothelial cells.ConclusionsCoronary and brachial endothelial dysfunction was evident in Y-T2D who were within 5 years of diagnosis and did not have severe hyperglycemia or dyslipidemia. Plasma-derived small extracellular vesicles induced markers of endothelial dysfunction, which corroborated accelerated subclinical coronary atherosclerosis as an early feature in Y-T2D.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308 and NCT01399385.
| S-EPMC11361354 | biostudies-literature
Project description:PurposeMonogenic diabetes accounts for 1-2% of diabetes cases. It is often undiagnosed, which may lead to inappropriate treatment. This study was performed to estimate the prevalence of monogenic diabetes in a cohort of overweight/obese adolescents diagnosed with type 2 diabetes (T2D).MethodsSequencing using a custom monogenic diabetes gene panel was performed on a racially/ethnically diverse cohort of 488 overweight/obese adolescents with T2D in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial. Associations between having a monogenic diabetes variant and clinical characteristics and time to treatment failure were analyzed.ResultsMore than 4% (22/488) had genetic variants causing monogenic diabetes (seven GCK, seven HNF4A, five HNF1A, two INS, and one KLF11). Patients with monogenic diabetes had a statistically, but not clinically, significant lower body mass index (BMI) z-score, lower fasting insulin, and higher fasting glucose. Most (6/7) patients with HNF4A variants rapidly failed TODAY treatment across study arms (hazard ratio = 5.03, P = 0.0002), while none with GCK variants failed treatment.ConclusionThe finding of 4.5% of patients with monogenic diabetes in an overweight/obese cohort of children and adolescents with T2D suggests that monogenic diabetes diagnosis should be considered in children and adolescents without diabetes-associated autoantibodies and maintained C-peptide, regardless of BMI, as it may direct appropriate clinical management.
| S-EPMC5955780 | biostudies-literature
Project description:To determine the prevalence of retinopathy in 517 youth with type 2 diabetes of 2-8 years duration enrolled in the TODAY study.Retinal photographs were graded centrally for retinopathy using established standards.Retinopathy was identified in 13.7% of subjects. Prevalence increased with age, diabetes duration, and mean HbA1c. Subjects in the highest BMI tertile had the lowest prevalence of retinopathy.Prevalence of retinopathy and its association with HbA1c and diabetes duration is similar to that previously reported in youth with type 1 diabetes and in adults with type 2 diabetes of known duration. The mechanism underlying the reduced risk of retinopathy in the most obese individuals is unknown. Follow-up of this cohort will help define the natural history of retinopathy in youth with type 2 diabetes.
| S-EPMC3661825 | biostudies-literature
Project description:BackgroundDespite the increasing prevalence of type 2 diabetes in youth, there are few data to guide treatment. We compared the efficacy of three treatment regimens to achieve durable glycemic control in children and adolescents with recent-onset type 2 diabetes.MethodsEligible patients 10 to 17 years of age were treated with metformin (at a dose of 1000 mg twice daily) to attain a glycated hemoglobin level of less than 8% and were randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg twice a day) or a lifestyle-intervention program focusing on weight loss through eating and activity behaviors. The primary outcome was loss of glycemic control, defined as a glycated hemoglobin level of at least 8% for 6 months or sustained metabolic decompensation requiring insulin.ResultsOf the 699 randomly assigned participants (mean duration of diagnosed type 2 diabetes, 7.8 months), 319 (45.6%) reached the primary outcome over an average follow-up of 3.86 years. Rates of failure were 51.7% (120 of 232 participants), 38.6% (90 of 233), and 46.6% (109 of 234) for metformin alone, metformin plus rosiglitazone, and metformin plus lifestyle intervention, respectively. Metformin plus rosiglitazone was superior to metformin alone (P=0.006); metformin plus lifestyle intervention was intermediate but not significantly different from metformin alone or metformin plus rosiglitazone. Prespecified analyses according to sex and race or ethnic group showed differences in sustained effectiveness, with metformin alone least effective in non-Hispanic black participants and metformin plus rosiglitazone most effective in girls. Serious adverse events were reported in 19.2% of participants.ConclusionsMonotherapy with metformin was associated with durable glycemic control in approximately half of children and adolescents with type 2 diabetes. The addition of rosiglitazone, but not an intensive lifestyle intervention, was superior to metformin alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; TODAY ClinicalTrials.gov number, NCT00081328.).
| S-EPMC3478667 | biostudies-literature
Project description:The number of immunotherapeutic clinical trials in type 1 diabetes currently being conducted is expanding, and thus there is a need for robust immune-monitoring assays which are capable of detecting and characterizing islet specific immune responses in peripheral blood. Islet- specific T cells can serve as biomarkers and as such can guide drug selection, dosing regimens and immunological efficacy. Furthermore, these biomarkers can be utilized in patient stratification which can then benchmark suitability for participation in future clinical trials. This review focusses on the commonly used immune-monitoring techniques including multimer and antigen induced marker assays and the potential to combine these with single cell transcriptional profiling which may provide a greater understanding of the mechanisms underlying immuno-intervention. Although challenges remain around some key areas such as the need for harmonizing assays, technological advances mean that multiparametric information derived from a single sample can be used in coordinated efforts to harmonize biomarker discovery and validation. Moreover, the technologies discussed here have the potential to provide a unique insight on the effect of therapies on key players in the pathogenesis of T1D that cannot be obtained using antigen agnostic approaches.
| S-EPMC10240960 | biostudies-literature
Project description:AimsExamine associations of dietary strategies used to manage diabetes over time with hemoglobin A1c in youth-onset type 1 or type 2 diabetes.MethodsThe SEARCH for Diabetes in Youth observational study assessed dietary strategies used by 1814 participants with diabetes (n = 1558 type 1, n = 256 type 2) at two to three research visits over 5.5 years (range 1.7-12.2). Participants reported often, sometimes, or never using 10 different dietary strategies, and use over time was categorized into five mutually exclusive groups: often using across visits; started using at later visits; sometimes using across visits; stopped using at later visits; or never using across visits. General multivariable linear models evaluated most recent A1c by use category for each strategy.ResultsIn type 1 diabetes, A1c was lower among those who starting tracking calories (-0.4%, Tukey P < .05), often counted carbs (-0.8%, Tukey P < .001), or sometimes chose low glycemic index foods (-0.5%, Tukey P = .02) vs those with less use, while participants who never drank more milk had the lowest A1c (-0.5%, Tukey P = .04). In type 2 diabetes, A1c was lower among those who often limited high fat foods (-2.0%, Tukey P = .02) or started counting carbohydrates (-1.7%, Tukey P = .07) than those who did so less.ConclusionsFor several dietary strategies, more frequent use over time was related to lower A1c in youth-onset type 1 and type 2 diabetes, suggesting these strategies can likely support diabetes management for this population. Investigation into factors predicting receipt of advice for specific strategies and corresponding impact on intake might be considered.
| S-EPMC7855046 | biostudies-literature