semaglutide effects in obese youth with prediabetes/new onset type 2 diabetes and non-alcoholic fatty liver disease

Conditions: Type 2 Diabetes Mellitus; Impaired Glucose Tolerance; Non-Alcoholic Fatty Liver Disease; Obesity, Childhood

Summary: the purpose of this study is to understand the role of glp-1 in the pathogenesis of t2d in youth and explore their potential salutary effects and ability to delay the progressive loss of ß-cell function and reduce hepatic steatosis in youth with prediabetes/new onset t2d and nafld.

in a recent publication by the today group study, it was reported that "diabetes-related complications appear early in youth-onset t2d and accumulate rapidly at a mean age of 26.4 years," and 60.1% of participants developed at least one microvascular complication. the same has been reported in rise studies and was suggested that the rapid decline in β-cell function and its insensitivity to two of the most frequently used treatments for t2d in pediatrics is further aggravated by the rising prevalence in nafld. these alarming results indicate a pressing need for effective and innovative approaches at preserving β-cell function and reducing hepatic steatosis in obese youth in order to prevent disease progression and associated complications. this study will provide mechanistic insights in support of a glp-1 analog, semaglutide, 2.4 mg weekly, therapy for prediabetes, new onset t2d and nafld in youth. the study design is a randomized, double-blind, placebo-controlled, clinical trial (rct) using semaglutie (wegovy up to 2.4mg) for 6 months followed by a wash-out period of 3 months.

Eligibility criteria:
inclusion criteria * subjects diagnosed with pre-impaired glucose tolerance (pre-igt) (2h glucose ≥ 130 mg/dl to ≤ 200 mg/dl post-ogtt) or impaired glucose tolerance (2h glucose ≥140 to \ 200 and hba1c \>6.5% to10%) treated with stable metformin dose (stable metformin dose is defined as at least 1000 mg daily or the maximum tolerated dose for 12 months or less) * pdff of ≥ 8% * male or female, aged 10 to \<21 years at the day of randomization, in puberty (pubertal stage will be assessed by pediatric endocrinologists dr. samuels and dr. hu) (girls and boys: tanner stage ii-iv); girls who begin menstruating must have a negative pregnancy test during the study * weight ≥ 54kg * bmi ≥ 85% but ≤ 40 kg/m2 * good general health (normal kidney function, amylase, and lipase levels) * informed consent from a legally acceptable representative (lar) and child assent from the subject obtained before any trial-related activities (trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial) * ability and willingness to adhere to the protocol including self-measurement of plasma glucose according to the protocol. exclusion criteria * known or suspected hypersensitivity to trial product(s) or related products. * receipt of any investigational medicinal product within 30 days before screening. * prepubertal participants (tanner stage 1) * female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not using highly effective contraceptive methods. * having a diagnosis of: * type 1 diabetes o maturity onset diabetes of the young (mody) o history or presence of pancreatitis (acute or chronic) o presence of endocrinopathies (e.g., cushing syndrome) o cardiac, renal or pulmonary or other chronic illness o known history of heart disease (including history of clinically significant arrhythmias or conduction delays on ecg, or new clinically significant arrhythmias or conduction delays on ecg identified at visit 1) o family or personal history of men type 2 or medullary thyroid carcinoma (family is defined as a first-degree relative)o any other disorder which, in the opinion of the investigator, might jeopardize subject's safety or compliance with the protocol * any laboratory safety parameter at screening outside the below extended laboratory ranges: o baseline creatinine \>1.0mg o hypertriglyceridemia)(\>500 mg/dl) * calcitonin equal or above 50 ng/l at screening o body mass index (bmi) ≤ 25.0 at the screening visit o alt ≥5 times the upper normal limit (unl) o creatinine \>unl for age in children unless renal function is proven normal by further assessments at the discretion of the investigator * known hypoglycemic unawareness. * recurrent severe hypoglycemic episodes within the last year as judged by the investigator. * uncontrolled hypertension treated or untreated \>99th percentile for age and gender in children and adolescents. * treatment with any medication for the indication of diabetes other than stated in the inclusion criteria in a period of 90 days before screening. * taking medication, based on the investigator's judgement, that may cause significant weight gain or loss (e.g., antipsychotic, steroid, anti-obesity medication). * presence or history of malignant neoplasm within 5 years prior to the day of screening.basal and squamous cell skin cancer and any carcinoma in-situ is allowed. * positive insulinoma associated-protein 2 (ia-2) antibodies or anti-glutamic acid decarboxylase (anti-gad) antibodies. mental health: * history of major depressive disorder within 2 years before screening * diagnosis of other severe psychiatric disorders (e.g., schizophrenia, bipolar disorder) * a patient health questionnaire-9 (phq-9) score of ≥15 at screening * a lifetime history of suicidal attempt * suicidal behavior within 30 days before screening * suicidal ideation corresponding to type 4 or 5 based on the columbia-suicide severity * rating scale (c-ssrs) within the past 30 days before screening * participants with confirmed diagnosis of bulimia nervosa disorder

Keywords: prediabetes nafld impaired glucose tolerance semaglutide