Glucagon-like Peptide-1 Agonism With Very Low Calorie Diets

Study Overview
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Brief Summary
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The very-low calorie diet (VLCD) is a highly effective and safe way to rapidly lose significant amounts of weight and dramatically improve blood sugar control in a short period of time (typically 8-12 weeks). It has recently become recommended by the UK National Health Service as a treatment for selected patients with type 2 diabetes. One drawback of VLCD however is the associated loss of skeletal muscle which affects some patients. Semaglutide is a well-known medication for type 2 diabetes that also improves blood sugar control and facilitates weight loss. Recent research has shown that it may also stimulate muscle growth, meaning it could help to preserve muscle mass during weight loss. Therefore, this research study aims to see whether taking Semaglutide alongside the VLCD reduces the amount of muscle lost, and could improve the long-term outcomes of VLCD. The study will take place in the Medical School building in the Royal Derby Hospital. Up to 45 participants will be recruited and allocated into one of 3 groups: Semaglutide only VLCD only Combined Semaglutide plus VLCD The study is 12 weeks in duration and consists of four visits including two 6-hour visits, one 4-hour visit and one 30-minute visit. The first visit is a short Preliminary Visit where participants are asked to ingest stable isotope drinks for measurement of muscle growth rates and muscle mass. Food intake and physical activity monitoring will also be commenced. Visits 1 & 3 are identical and occur at the beginning and end of the 12-week intervention period, respectively. During these visits participants will undergo a Dual-energy X-ray absorptiometry (DXA) scan, a right vastus lateralis muscle ultrasound scan & muscle biopsy, an intravenous glucose tolerance test, electromyography, tests of muscular function, gait & balance, and questionnaires regarding quality of life & physical activity. These visits are expected to last up to 6 hours. Visit 2 is a shorter visit mid-way through the 12 weeks, lasting approximately 4.5 hours. Participants will undergo another DXA scan and muscle biopsy in addition to having multiple blood tests taken over a 4-hour period to determine muscle protein breakdown rates. During the 12 weeks, those in the VLCD group will be asked to stick strictly to an 800 kilocalorie very-low calorie diet, whilst those in the Semaglutide group will be required to inject themselves with Semaglutide once a week. Those in the combined group will be asked to do both. All participants will be monitored closely throughout the 12-week period, with regular phone calls and/or emails.

Official Title
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The Anabolic Effects of GLP-1 Agonism to Prevent Lean Muscle Losses During Very-low Calorie Diets (VLCDs) for Weight Loss

Conditions
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Type 2 Diabetes Mellitus in Obese

Intervention / Treatment
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* Drug: Semaglutide Pen Injector [Ozempic]
* Dietary Supplement: Very-low Calorie Diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed Type 2 Diabetes Mellitus Body mass index > 27kg·m-2 Eligible for VLCD, Semaglutide (or both), within routine practice Ability to provide informed consent Exclusion Criteria: BMI > 50kg·m-2 Current pregnancy or breastfeeding, or intention to fall pregnant within the next 3 months Uncontrolled hypertension (blood pressure >200/120mmHg) Current treatment with insulin Current or recent use of GLP-1 agonists Previous adverse reaction to a GLP-1 agonist Current or recent involvement in a VLCD programme (within the last 12 months) History of >5% weight loss within the preceding 12 months Ingestion of exogenous D2O within the preceding 12 months Background of clinically significant cardiovascular, cerebrovascular or respiratory disease, neurological disorders or musculoskeletal problems History of malignancy undergoing current treatment or palliation History of any medical condition contraindicating the use of GLP-1 agonist medication Any other medical condition deemed by the investigators to preclude inclusion into the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: VLCD only<br>Participants in this group will be placed on a very-low calorie diet with a daily energy intake limit of 800 kilocalories. 600 kilocalories will be made up of total meal replacement products supplied by Lighterlife UK. The remaining 200 kilocalories will be flexible for participants to add additional vegetables to supplement the total meal replacement products, allowing some variety to the diet. | Dietary Supplement: Very-low Calorie Diet<br>* Total meal replacement with a limit of 800 kilocalories per day<br>|
| Active Comparator: Semaglutide only<br>Participants will be asked to self-administer the GLP-1 agonist Semaglutide weekly, as per clinical practice. They will be asked to start at 0.25mg and increase every two weeks (if tolerated) to the maintenance dose of 1mg, which they will continue until the end of the study. | Drug: Semaglutide Pen Injector [Ozempic]<br>* Glucagon-like peptide 1 (GLP-1) receptor agonist<br>|
| Experimental: Combined VLCD plus Semaglutide<br>Participants in this group will both partake in the VLCD, and take the weekly dose of Semaglutide (as described above). | Drug: Semaglutide Pen Injector [Ozempic]<br>* Glucagon-like peptide 1 (GLP-1) receptor agonist<br>Dietary Supplement: Very-low Calorie Diet<br>* Total meal replacement with a limit of 800 kilocalories per day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Muscle protein synthesis rate | Measuring the rate of skeletal muscle growth in vivo by determining the rate of deuterium incorporation into muscle | 6 weeks | 
| Muscle protein breakdown rate | Measuring the rate of breakdown of skeletal muscle in vivo using the rate of appearance of deuterium-labelled 3-methyl-histidine in blood after an initial oral bolus | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Skeletal muscle mass | Determined from DXA scanning (measured in kg and percentage of total body weight) and novel techniques using rate of appearance of a creatine tracer in urine after an initial bolus | 12 weeks | 
| Fat mass | Determined from DXA scanning (measured in kg and percentage of total body weight) | 12 weeks | 
| Total body weight | Measured in kg | 12 weeks | 
| Whole body insulin sensitivity | Determined using the intravenous glucose tolerance test and measures of fasting insulin & glucose | 12 weeks | 
| Pancreatic beta cell function | Determined using the intravenous glucose tolerance test and measures of fasting insulin & glucose | 12 weeks | 
| Skeletal muscle strength | Determined from maximal voluntary contraction (MVC) of left knee extension | 12 weeks | 
| Skeletal neuromuscular function | Assessed using measurement of force stability during electromyography | 12 weeks | 
| Gross skeletal muscle function | Measured using a short battery of physical performance tests (SBPPT) to give an overall score of skeletal gross skeletal muscle function (scored out of 12) | 12 weeks | 
| Right vastus lateralis muscle thickness | Determined from muscle ultrasonography | 12 weeks | 
| Right vastus lateralis muscle cross sectional area (CSA) | Determined from muscle ultrasonography | 12 weeks | 
| Right vastus lateralis muscle fibre pennation angle | Determined from muscle ultrasonography | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes, Obesity, GLP-1, Semaglutide, VLCD