Semaglutide as an Adjunct to Dieting in the Treatment of Type 2 Diabetes

Study Overview
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Brief Summary
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The pharmacological approaches in the treatment of type 2 diabetes (T2DM) have advanced radically during the last decades. However, focus on long-term management of body weight, which is an essential part of treatment success, is often lacking. Excluding surgery, there are only a few effective treatment methods for obesity. Management of obesity is also greatly challenged by weight regain, which is common after a successful lifestyle intervention. Weight regain typically results in the deterioration of glucose homeostasis in T2DM. However, understanding the pathomechanisms of weight regain and subsequent worsening of glucose homeostasis is still insufficient. Therefore, T2DM treatment programs that target long-term weight management have been scarce. This study aims to fill the gaps in the current knowledge by advancing the development of treatment programs for T2DM that simultaneously head for improved glucose metabolism and improved long-term body weight control.

Detailed Description
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In this randomized, double-blind, parallel, placebo-controlled trial we compare the effects of semaglutide 1.34 mg/ml vs. normal dieting by randomizing the patients with both T2DM and overweight/obesity (BMI ≥27) (n=50, aged ≥18 to < 65 years) to two groups: both groups participate in a similar lifestyle treatment to induce weight loss, but one group gets an add-on of semaglutide 1.34mg/ml while the other is treated with placebo. Additionally, a reference group of healthy normal weight non-diabetic individuals (BMI ≤ 25 kg/m2, n=25, aged ≥18 to < 65 years) are included as controls at the initiation of the study.

Official Title
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Semaglutide as an Adjunct to Dieting in the Treatment of Type 2 Diabetes - Effects on Glucose Metabolism, Prevention of Weight Regain and Peripheral Tissue Metabolic Activation

Conditions
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Type2 Diabetes

Intervention / Treatment
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* Drug: Semaglutide, 1.34 mg/mL
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years and <65 years BMI: ≥27 kg/m2 T2DM (HbA1c ≥ 6.0% if on anti-diabetic medication or HbA1c≥6.5% if non- medicated) Participant is willing and able to give informed consent for participation in the study Exclusion Criteria: Contraindication to trial drugs Use of insulin or GLP-1RAs (during the past 3 months) Use of anti-obesity drugs (during the past 3 months) Weight change of >5% during the past 3 months Bariatric surgery or planned bariatric surgery during the trial History of pancreatitis Impaired renal function (GFR<30 ml/min/1.73m2) Impaired hepatic function (ALAT>2 x upper limit normal) Clinically significant active cardiovascular disease Clinically significant abnormality in the ECG Cancer (except basal or squamous cell skin cancers) Major psychiatric disease (such as severe depression, bipolar disorder, schizophrenia) Substance abuse Learning disability Females of childbearing potential not using adequate contraceptive methods Pregnancy Lactation Any other condition that in the opinion of the investigator could interfere with the conduction of the study or interpretation of the study results

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Semaglutide<br>The intervention study for the patients with T2DM begins with a low-calorie diet (LCD) phase run-in for 13 weeks. During re-introduction of food, the participants will be assigned to semaglutide 1.34mg/ml treatment for 44 weeks (dose escalation in total 8 weeks, maintenance period for 36 weeks). | Drug: Semaglutide, 1.34 mg/mL<br>* The low-calorie diet (LCD) has a phase run-in period for 13 weeks for all participants including 8 weeks of total LCD followed 5-week gradual re-introduction of food (replacement of the VLCD products by one meal/week). During re-introduction of food, the subjects will be randomly assigned to semaglutide 1.34mg/ml (subcutaneous administration, dose escalation 0.25 mg once weekly for 4 weeks, 0.5 mg once weekly for 4 weeks, where after 1.0 mg once weekly) until the end of the study (12 months). The participants will receive lifestyle counselling throughout the study.<br>* Other names: Ozempic;|
| Placebo Comparator: Placebo<br>The intervention study for the patients with T2DM begins with a low-calorie diet (LCD) phase run-in for 13 weeks. During re-introduction of food, the participants will be assigned to placebo treatment for 44 weeks (dose escalation in total 8 weeks, maintenance period for 36 weeks). | Drug: Placebo<br>* The low-calorie diet (LCD) has a phase run-in period for 13 weeks for all participants including 8 weeks of total LCD followed 5-week gradual re-introduction of food (replacement of the VLCD products by one meal/week). During re-introduction of food, the subjects will be randomly assigned to placebo (subcutaneous administration, dose escalation 0.25 mg once weekly for 4 weeks, 0.5 mg once weekly for 4 weeks, where after 1.0 mg once weekly) until the end of the study (12 months). The participants will receive lifestyle counselling throughout the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c | Change in HbA1c (%) | from baseline to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c | Change in HbA1c (%) | from baseline to 6 months | 
| Fasting plasma glucose | Change in fasting plasma glucose (mmol/l) | from baseline to 6 and 12 months | 
| Body weight | Change in body weight (kg) | from baseline to 6 and 12 months | 
| Percentage of patients reaching ≥5%,10% & 15% weight loss |  | from baseline to 6 and 12 months | 
| Waist circumference | Change in waist circumference (cm) | from baseline to 6 and 12 months | 
| Change in appetite and eating habits, control of eating | Using questionnaire Control of Eating (CoEQ) | from baseline to 6 and 12 months | 
| Change in appetite and eating habits, binge eating | Using questionnaires Binge Eating Scale(BES), Questionnaire on Eating and Weight Patterns (QEWP) | from baseline to 6 and 12 months | 
| Change in appetite and eating habits, emotional, external and restraint eating | Using questionnaire Dutch Eating Behaviour Questionnaire (DEBQ) | from baseline to 6 and 12 months | 
| Blood pressure | Change in blood pressure (mmHg) | from baseline to 6 and 12 months | 
| Plasma lipids | Change in lipids (total cholesterol, LDL, HDL, TAG) (mmol/l) | from baseline to 6 and 12 months | 
| Changes in concomitant antidiabetic medications | Change in number of antidiabetic medications | from baseline to 6 and 12 months | 
| Changes in concomitant antihypertensive medications | Change in number of antihypertensive medications | from baseline to 6 and 12 months | 
| Changes in concomitant lipid medications | Change in number of lipid medications | from baseline to 6 and 12 months | 
| Mitochondrial DNA quantification | Change in mitochondrial DNA (mtDNA) copy number, RNA expression of mtDNA encoded genes in adipose tissue and skeletal muscle | from baseline to 6 and 12 months | 
| Change in the transcriptomics profile of adipose tissue and skeletal muscle | Change in the transcriptomics profile by qPCR and/or RNA sequencing | from baseline to 6 and 12 months | 
| Change in the oxygen uptake and perfusion in subcutaneous and intra-abdominal adipose tissue, brown adipose tissue, skeletal muscle, gut and liver | Change in the oxygen uptake and perfusion measured by PET/CT (in vivo) | from baseline to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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weight loss, dieting