Glucagon-like Peptide-1 Agonism With Very Low Calorie Diets (SemVLCD)

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

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:

1. Semaglutide only
2. VLCD only
3. 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.

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes Mellitus in Obese
• Intervention / Treatment: Dietary supplement: Very-low Calorie Diet; Drug: Semaglutide Pen Injector [Ozempic]

• Study Type: Interventional
• Enrollment (Anticipated): 45
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • Derby, United Kingdom, DE22 3DT
    • Recruiting
    • University of Nottingham, Royal Derby Hospital Centre
    • Contact: Philip Atherton, BSc MSc PhD; Phone Number: 01332724622; Email: philip.atherton@nottingham.ac.uk
    • Principal Investigator: Iskandar Idris
    • Sub-Investigator: Oluwaseun Anyiam
    • Sub-Investigator: Kenneth Smith
    • Sub-Investigator: Beth Phillips
    • Sub-Investigator: Dan Wilkinson

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: VLCD only; 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; Total meal replacement with a limit of 800 kilocalories per day
Active Comparator: Semaglutide only; 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]; Glucagon-like peptide 1 (GLP-1) receptor agonist
Experimental: Combined VLCD plus Semaglutide; Participants in this group will both partake in the VLCD, and take the weekly dose of Semaglutide (as described above).	Dietary supplement: Very-low Calorie Diet; Total meal replacement with a limit of 800 kilocalories per day; Drug: Semaglutide Pen Injector [Ozempic]; Glucagon-like peptide 1 (GLP-1) receptor agonist

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Nottingham
• Collaborators: Medical Research Council
• Investigators: Principal Investigator: Iskandar Idris, Professor in Diabetes and Vascular Medicine & Honorary Consultant

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2021
• Primary Completion (Anticipated): July 28, 2023
• Study Completion (Anticipated): July 28, 2023

Study Registration Dates

• First Submitted: May 23, 2022
• First Submitted That Met QC Criteria: October 31, 2022
• First Posted (Actual): November 4, 2022

Study Record Updates

• Last Update Posted (Actual): November 4, 2022
• Last Update Submitted That Met QC Criteria: October 31, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Obesity; GLP-1; Type 2 diabetes; Semaglutide; VLCD
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: 21031

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No