Exenatide Effects on Cardiometabolic Risk and Weight in Adolescents with Morbid Obesity and Type 2 Diabetes Mellitus: Two Case Reports.

Objective Glucagon-like peptide-1 (GLP-1) receptor agonists improve glycemic control and cardiometabolic risk factors in adults with type 2 diabetes mellitus, but pediatric data is sparse. Research design and methods This is the first report to describe the effects of GLP-1 receptor agonist Exenatide on metabolic risk and weight in adolescents with morbid obesity (BMI>35kg/m2) and type 2 diabetes in the first 6 months after treatment initiation. Two patients with morbid obesity who failed conventional therapy with insulin glargine and Metformin were treated with the addition of Exenatide. Metabolic parameters were obtained at 3 and 6 months post intervention. Results Improvements in cardiometabolic risk factors, such as fasting glucose and triglyceride levels, as well as HbA1c, were reached at 6 months compared to baseline. Conclusions Our cases highlight the therapeutic potential of exenatide for adolescent patients with morbid obesity and type 2 diabetes.


Introduction
Glucagon-like peptide-1 (GLP-1) receptor agonist Exenatide is an incretin mimetic approved by the US Food and Drug Administration in 2005 as an adjunct to diet and exercise for glycemic control in adults with type 2 diabetes. Improvements in cardiometabolic risk factors and weight in type 2 diabetes patients using Exenatide are well described in adults; however, reports in adolescents are limited to non-diabetic youth with obesity [1,2]. Given This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. that GLP-1 agonist liraglutide, a medication for type 2 diabetes, has recently been approved by the FDA as the first injectable drug approved for the treatment of obesity, it is important to evaluate the effects of available options in this class of injectable medications. We report the first two cases of Exenatide therapy in adolescents with morbid obesity and type 2 diabetes to document improvement in cardiometabolic parameters as well as glycemic control within 6 months of therapy initiation.

Research Design and Methods
Anthropometric measures (weight, waist circumference (WC), body mass index (BMI)) and blood pressure (BP) were measured as previously reported [3] at baseline prior to Exenatide treatment, and at 3 and 6 months post intervention. Blood samples were obtained between the hours of 8:00 and 10:00 AM at initial preoperative bariatric surgery evaluation after an overnight fast. A 75 gram, 2-hour oral glucose tolerance test (OGTT) was performed with insulin and glucose samples obtained at 0, 30, 60, and 120 minutes. Glucose, lipids, HbA1c, liver function tests, and basic metabolic panel were performed at the laboratory of New York Presbyterian Hospital. Insulin's were performed at Esoterix Laboratories, Calabasas, CA.

Case 1
A 16 year old Hispanic female was diagnosed with type 2 diabetes 24 months after laparoscopic adjustable gastric banding (LAGB). She presented to the Center for Adolescent Bariatric Surgery (CABS) for evaluation of severe morbid obesity with BMI 86.2kg/m 2 (weight 201.7kg, height 153cm) and underwent LAGB at age 14 years 3 months. Weight problems were present from early infancy. She had Blount's disease requiring 5 surgical procedures to correct leg bowing and remained with limited mobility. Family history was notable for type 2 diabetes, hypertension, and stroke.
At initial preoperative visit, laboratory evaluation revealed metabolic syndrome with hypertriglyceridemia (170mg/dl), low high-density lipoprotein (HDL) 35mg/dl, impaired fasting glucose (IFG) 106mg/dl, and increased WC 188cm in addition to impaired glucose tolerance (140mg/dl) with HbA1c 6.5% and c-reactive protein (CRP) 46.2mg/dl. Following surgery, she lost 13.2kg over 6 weeks, but by 24 months post-operatively, her weight had increased to 17.4kg above her preoperative weight. A 2-hour OGTT demonstrated fasting glucose (FG) 188mg/dl, 2 hour glucose 293mg/dl and HbA1c 8.8% resulting in the diagnosis of type 2 diabetes. Metformin 850mg BID and Lantus 10 units were started, but she self discontinued Metformin due to gastrointestinal side effects.
With her weight 207.2kgs, HbA1c 11.2% and FG 297mg/dl, Exenatide 2mg once weekly (QW) was added to her Lantus and metformin regimen. At 3 months, her weight decreased to 198.9kgs (−8.3kgs) and FG decreased to 160mg/dl (−137). By 6 months, HbA1c substantially decreased to 8.4% with FG 103mg/dl and reached 7.6% by 9 months post therapy with stabilization of weight at 199.3kgs.

Case 2
A 14 year old Hispanic female with a 3 year history of type 2 diabetes on once-daily DPP-4 inhibitor Sitagliptin presented for evaluation of morbid obesity with asthma, obstructive sleep apnea, reflux, and irregular menses. She was overweight since preschool age. Family history was notable for type 2 diabetes, obesity, hypertension, hyperlipidemia, and cholelithiasis.

Conclusions
These are the first two cases in adolescents with morbid obesity and type 2 diabetes mellitus to document 6 month effects on cardiometabolic risk factors, weight, and glycemic control with GLP-1 receptor agonist Exenatide therapy. Improvements in metabolic parameters, HbA1c and weight have previously been documented in adult populations with type 2 diabetes. However, there is scarce longitudinal data pertaining to the pediatric population limited to two studies in non diabetic youth with obesity.
In a randomized, clinical trial by the same group, 26 adolescents 12-19 years old with severe obesity without diabetes were randomized to either three months of Exenatide or placebo then three months of open-label extension with Exenatide for all. Compliance was excellent and medication was well tolerated with mild to moderate events such as nausea (62% in Exenatide group vs. 31% in placebo group), abdominal pain (15% vs 23%), diarrhea (8% vs 31%), headache (23% vs 46%), and vomiting (31% vs 8%) with no episodes of hypoglycemia or pancreatitis. Compared to placebo, the Exenatide group had greater reduction in BMI (−1.13kg/m 2 , p=0.02), weight (−3.26kg, p=0.02) and final BMI of −4% after the 3 month open label extension with trend towards reduction in HbA1c (−0.11%, p=0.07) [2].
Our findings with Exenatide highlight the therapeutic potential of Exenatide and extend to the morbidly obese adolescent type 2 diabetes patient population previously described data regarding improvement in cardiometabolic risk factors in adults and in non-diabetic, obese adolescent patients. These findings suggest that Exenatide therapy may offer an additional treatment option that should be evaluated in larger, well-controlled trials of adolescent type 2 diabetes patients with morbid obesity.