Diabetes, Effects of Liraglutide Administration on Brain Activity, Hunger, Weight Loss
Conditions
Keywords
fMRI, Liraglutide, diabetes, GLP-1
Brief summary
The main purpose of this study is to help us understand the effects of diabetes medication Liraglutide on weight loss and hunger. The investigators have already determined what the highest tolerated dose of Liraglutide is through earlier human research studies. Liraglutide was approved by the FDA in January 2010 for treatment of diabetes. The investigators will also study the following: 1. The impact of Liraglutide on brain responses to food 2. It's effect on physiological and mental performance 3. If its effect on the brain differs among obese and lean diabetic subjects.
Detailed description
This is a randomized, placebo controlled, cross-over, double-blinded study to assess the effects of liraglutide on brain activation in areas involved in cognitive control and reward during food visualization. Study participation will span approximately 1.5-2 months. Subjects will learn to self-administer the medication and will have a total of 8 study visits plus one screening visit. The visits will include the following tests/procedures: 1. Vital signs (blood pressure, temperature, heart rate, breathing rate) 2. Height, weight and other body measurements like waist 3. Blood tests 4. Urine pregnancy test (women only) 5. Electrocardiogram (EKG) 6. Medical history 7. Physical exam 8. Body Composition tests 9. Study logs to record food intake and blood sugar 10. functional MRI We plan to recruit a total of 24 subjects to be treated with placebo and liraglutide. We propose to enroll 12 obese diabetic (type 2) and 12 lean diabetic (type 2) subjects. Equal numbers of men and women will be enrolled and the randomization will block for gender.
Interventions
DRUGLiraglutide
In the experimental arm of this randomized, placebo controlled, cross-over, double-blinded study to assess the effects of liraglutide. Subjects will self-inject Liraglutide once per day for 18 days. Subjects will start the treatment with a dose of 0.6 mg for the first week, then 1.2 mg for the second week and 1.8 mg for 3 days in the third week.
DRUGPlacebo
In the placebo arm of this randomized, placebo controlled, cross-over, double-blinded study to assess the effects of liraglutide. Subjects will self-inject placebo once per day for 18 days.
Sponsors
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Subjects will be men and women between the ages of 18 and 65. The following table list inclusion criteria for each group (lean diabetic and obese diabetic). Subjects must meet either HbA1c or fasting plasma glucose (FPG) criteria. Lean diabetic: BMI: 18-25 kg/m2 HbA1c: \< 8.9% Fasting plasma glucose: \<250 mg/dL Other inclusion criteria: On dietary modification and/or metformin Obese diabetic: BMI: \>27 kg/m2 HbA1c: \< 8.9% Fasting plasma glucose: \<250 mg/dL Other inclusion criteria: On dietary modification and/or metformin Additionally, women participants must use double barrier methods to prevent pregnancy (diaphragm with intravaginal spermicide, cervical cap, male or female condom with spermicide). If a woman suspects that she has become pregnant at any time or does not use one of the contraceptive methods recommended by the investigator, she must notify the study staff. If a woman becomes pregnant, she will be withdrawn from the study. The study staff will follow the progress of her pregnancy and the birth of her child.
Exclusion criteria
1. Uncontrolled diabetes (HbA1c\>8.9%, or FPG\>250 mg/dL) 2. Women who are breastfeeding, pregnant, or wanting to become pregnant. 3. Women using IUD 4. Any change in the dosage of hormonal contraceptive medications (birth control pills, implanon). Subjects should remain on same medication/ same dose during the time of the entire study. 5. Moderate (creatinine clearance of 30-59 ml/min) and severe renal impairment (creatinine clearance below 30 ml/min) and end-stage renal disease 6. Moderate, or severe hepatic impairment 7. Hypersensitivity to the active substance or any of the excipients in liraglutide 8. History of diabetic ketoacidosis 9. Congestive heart failure 10. Inflammatory conditions like inflammatory bowel disease, Rheumatoid arthritis etc 11. Gastroparesis 12. Pancreatitis 13. Gallstones- as they may cause increased risk of pancreatitis 14. Alcohol consumption- the maximum quantity for men is 140g-210g per week. For women, the range is 84g-140g per week or drinking as consuming no more than two drinks a day for men and one for women. Alcohol can cause increased risk of pancreatitis and hypoglycemia. 15. Untreated thyroid disease like hypothyroidism or hyperthyroidism 16. Subjects taking the following medications: warfarin, steroids (inhaled or systemic due to reduced hypoglycemic effect), and subjects on other hormones (LHRH analogs etc). 17. Subjects on any oral anti-diabetic agent except metformin 18. Personal or family history of MEN II or medullary thyroid cancer 19. Subjects with any type of bioimplant activated by mechanical, electronic, or magnetic means (e.g. cochlear implants, pacemakers, neuron or biostimulators, electronic infusion pumps, etc.) 20. Subjects with any type of metallic implant that could potentially be displaced or damaged during MRI, such as aneurysm clips, metallic skull plates, surgical implants etc. or metal containing tattoos 21. Anxiety and/or claustrophobia 22. Uncontrolled cardiac impairment, circulatory impairment, or inability to perspire (poor thermoregulatory function) 23. Significant sensory or motor impairment 24. Epilepsy, particularly photo-sensitive epilepsy, which may place the individual at a higher risk for adverse events during fMRI scanning with visual stimulation 25. Subjects with neurological problems which may interfere with or complicate testing (e.g. presence of titubation) 26. Body weight above the limitation of the MRI scanning table (330lbs/150 Kg) or body dimensions that could difficult the performance of the scan. 27. Subjects who cannot adhere to the experimental protocol for any reason 28. Anemia with Hgb less than 10 29. Uncontrolled infectious diseases (e.g. HIV, hepatitis, chronic infections etc) 30. Any uncontrolled endocrine condition, e.g Cushing's, Acromegaly, etc 31. Any cancers or lymphoma 32. Eating disorders like anorexia, bulimia 33. Severe hypertriglyceridemia (triglycerides \>500 mg/dl) 34. Weight loss surgery or gastrectomy 35. Any changes in medications that affect brain function, e.g. anti-depressants, anti-psychotics, anti-anxiety, anti-seizure medications, antihypertensives etc (subjects should remain on same medication/ same dose during the time of the entire study). 36. Irregular periods, defined as cycle length less than 22 days or more than 40 days. 37. Any change in smoking status. 38. Vegetarians- as food images presented will include numerous non-vegetarian items and thus will not be appealing as high calorie food items.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change Between Highly Desirable vs. Less Desirable Food Cues in the Effect Size of Cortical Activation During Food Visualization | 18 days of Liraglutide or placebo treatment | Effect size (region of interest z-scores, derived from z-maps of the brain) shown below is the difference in parietal cortex activation to highly desirable (high fat or high calorie, e.g. cakes, pies, fries) versus less desirable (low fat or low calorie, e.g. vegetables, fruits) food cues for each treatment condition (liraglutide or placebo) at the end of the treatment period. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Liraglutide First, Then Placebo 14 participants were randomized to receive Liraglutide and then were cross-overed to receive placebo | 14 |
| Placebo First, Then Liraglutide 14 participants were randomized to receive Placebo and then were cross-overed to receive Liraglutide | 14 |
| Total | 28 |
Baseline characteristics
| Characteristic | Placebo First, Then Liraglutide | Liraglutide First, Then Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 14 Participants | 28 Participants |
| Age, Continuous | 52.5 years STANDARD_DEVIATION 10.5 | 52.5 years STANDARD_DEVIATION 10.5 | 52.5 years STANDARD_DEVIATION 10.5 |
| Region of Enrollment United States | 14 participants | 14 participants | 28 participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 12 Participants |
| Sex: Female, Male Male | 9 Participants | 7 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 28 | 7 / 28 |
| serious Total, serious adverse events | 0 / 28 | 0 / 28 |
Outcome results
Primary
Change Between Highly Desirable vs. Less Desirable Food Cues in the Effect Size of Cortical Activation During Food Visualization
Effect size (region of interest z-scores, derived from z-maps of the brain) shown below is the difference in parietal cortex activation to highly desirable (high fat or high calorie, e.g. cakes, pies, fries) versus less desirable (low fat or low calorie, e.g. vegetables, fruits) food cues for each treatment condition (liraglutide or placebo) at the end of the treatment period.
Time frame: 18 days of Liraglutide or placebo treatment
Population: Participants with incomplete MRI scans were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide | Change Between Highly Desirable vs. Less Desirable Food Cues in the Effect Size of Cortical Activation During Food Visualization | -0.42 z-scores of activation in cortex | Standard Error 0.27 |
| Placebo | Change Between Highly Desirable vs. Less Desirable Food Cues in the Effect Size of Cortical Activation During Food Visualization | 0.53 z-scores of activation in cortex | Standard Error 0.37 |