Semaglutide Effects in Obese Youth With Prediabetes/New Onset Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease

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 mg/dl post-OGTT OR HbA1c ≥5.7% to \<6.5%), OR new-onset T2D (≤24 months duration, 2h glucose \>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