CMBD: Changes in Bone Turnover With Exposure to a GLP-1 Receptor Agonist
Study Details
Study Description
Brief Summary
The purpose of this study is to determine changes in bone turnover markers and calcitonin following the initiation of exenatide compared to placebo in postmenopausal women wtih type 2 diabetes.
Hypothesis 1a: Bone resorption (measured by osteocalcin and bone-specific alkaline phosphatase) will be lower and bone formation (measured by type I collagen crosslinked aminoterminal peptide in urine (Urine NTX)) will be higher when subjects are treated with exenatide compared to when subjects are treated with placebo.
Hypothesis 1b: Calcitonin levels will not vary significantly between periods of treatment with exenatide vs. placebo.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 4 |
Detailed Description
Patients with Type 2 Diabetes Mellitus (T2DM) are at an increased risk of fracture, despite having bone mineral density (BMD) levels similar to age and sex matched cohorts. Recent studies have indicated that changes in incretin (INtestinal seCRETion of INsulin) hormones in the setting of T2DM may play a role in bone metabolism. Two of these incretin hormones, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have been shown to be involved in bone turnover regulation, in addition to their effect in increasing insulin secretion and decreasing glucagon secretion in a glucose-dependent manner. In addition, the rise in glucagon-like peptide-2 (GLP-2) in the postprandial state has been found to have a direct effect on reduced bone resorption in a non-fasting state and treatment with GLP-2 improved BMD in postmenopausal women. Due to their glucose lowering effects, incretin hormones have been a therapeutic target for the treatment of T2DM through GLP-1 receptor agonists (i.e. exenatide) or inhibition of incretin hormone metabolism via dipeptidyl peptidase 4 (DPP-4)inhibitors. The GLP-1 receptor analog exenatide leads to an approximate 13-fold increased GLP-1 effect compared to approximate doubling of incretin hormone levels with current DDP-4 inhibitors. In rodent models, calcitonin levels rise significantly following treatment with GLP-1 receptor agonists, leading to c-cell hyperplasia. However, review of calcitonin changes in humans and cynomolgus monkeys treated with GLP-1 receptor agonists have not shown similar results.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Exenatide then Placebo Study participants in phase1 will receive the study drug, exenatide, at a dose of 5mg subcutaneously twice daily 30 minutes before meals for one month. During the second month of the study, the dose of exenatide will be increased to 10mg subcutaneously twice daily before meals for one month. During the third month of the study, no study medication will be given and this will serve as a "wash out" period prior to the second phase of the study (placebo). During the fourth and fifth months, study participants will get placebo alternatives to exenatide 5mg and exenatide 10mg, respectively, subcutaneously twice daily before meals. |
Drug: exenatide
exenatide 5mcg sq twice daily for one month and exenatide 10mcg twice daily for month 2. The 3rd month is a washout period. Month 4 and 5 saline placebo is given as 5mcg and 10mcg respectively.
Other Names:
Drug: Saline
Month 1 and 2 saline placebo is given as a low and high dose respectively. The 3rd month is a washout period. Month 4 exenatide 5mcg sq twice daily and for month 5 exenatide 10mcg twice daily is administered.
Other Names:
|
| Active Comparator: Placebo then Exenatide Study participants in phase1 will receive the saline placebo, at a dose of 5mcg subcutaneously twice daily 30 minutes before meals for one month. During the second month of the study, the saline placebo will be increased to 10mcg subcutaneously twice daily before meals for one month. During the third month of the study, no treatment will be given and this will serve as a "wash out" period prior to the second phase of the study. During the fourth month study participants will receive Exenatide 5mcg twice daily with meals. During the fifth month, study participants will receive exenatide 10mcg, subcutaneously twice daily before meals. |
Drug: exenatide
exenatide 5mcg sq twice daily for one month and exenatide 10mcg twice daily for month 2. The 3rd month is a washout period. Month 4 and 5 saline placebo is given as 5mcg and 10mcg respectively.
Other Names:
Drug: Saline
Month 1 and 2 saline placebo is given as a low and high dose respectively. The 3rd month is a washout period. Month 4 exenatide 5mcg sq twice daily and for month 5 exenatide 10mcg twice daily is administered.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Determine Changes in Bone Resorption Markers During the Treatment With a GLP-1 Receptor Agonist (Exenatide) Compared to Placebo in Patients With T2DM. [Baseline to 20 weeks]
Bone reabsorption by bone-specific alkaline phosphatase (BAP) was assessed. Distribution of the Difference between EX/PBO Low/High Dose and Baseline Levels were calculated.
- Determine Changes in Bone Turnover Markers by Serum N-Telo Peptide During the Treatment With a GLP-1 Receptor Agonist (Exenatide) Compared to Placebo in Patients With T2DM. [Baseline to 20 weeks]
Bone turnover by Serum N-Telo peptide (NTX) was assessed. Distribution of the Difference between EX/PBO Low/High Dose and Baseline Levels were calculated
- Determine Changes in Bone Turnover Markers by Tartrate-Resistant Acid Phosphatase 5b (TRACP5b) During the Treatment With a GLP-1 Receptor Agonist (Exenatide) Compared to Placebo in Patients With T2DM. [Baseline to 20 weeks]
Bone turnover by Tartrate-Resistant Acid Phosphatase 5b (TRACP5b) was assessed. Distribution of the Difference between EX/PBO Low/High Dose and Baseline Levels were calculated.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Postmenopausal women (as defined by age ≥45 years old or amenorrhea for >2years)
-
Type 2 DM currently not on diabetes-specific medication(s) or treated with monotherapy of metformin or a sulfonylurea. Patients treated with insulin monotherapy will also be eligible if the total daily dose of insulin is ≤10units. If on a medication for diabetes prior to study entry, the medication can be discontinued for 2 weeks prior to study initiation.
-
Hemoglobin A1c (HbA1c) of 6.5-9.0%
Exclusion Criteria:
-
Use of an incretin mimetic (i.e. exenatide, liraglutide), a DPP-4 inhibitor (i.e. sitagliptin, saxagliptin), a thiazolidinedione, or oral glucocorticoids in the 6 months prior to the study will not be eligible
-
Known osteoporosis or patients treated with an osteoporosis-specific medication (bisphosphonate, teriparatide) or estrogen (including Selective Estrogen Receptor Modulators (SERMs)) or those who anticipate imminent treatment with one of these medications will be excluded from the study
-
Chronic kidney disease (calculated GFR <30 ml/min) or a disease known to affect bone turnover (i.e. Paget Disease, Osteogenesis Imperfecta, HIV) will be excluded from the study.
-
History of pancreatitis
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Alabama at Birmingham | Birmingham | Alabama | United States | 35294 |
Sponsors and Collaborators
- University of Alabama at Birmingham
- Amylin Pharmaceuticals, LLC.
Investigators
- Principal Investigator: Amy Warriner, MD, University of Alabama at Birmingham
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- F100929001
Study Results
Participant Flow
| Recruitment Details | Protocol open to accrual: February 2011, primary completion date, August 2015 and study completion date August 2015. Recruitment location at UAB. Postmenopausal women with diabetes mellitus on no medications or metformin alone were recruited from a single outpatient clinic setting. |
|---|---|
| Pre-assignment Detail | Potential participants attended a screening visit to ensure they met inclusion/exclusion criteria. If they were on metformin at the screening visit, it was discontinued. They returned in 1 month for the baseline visit and randomization. |
| Arm/Group Title | Exenatide 1st Then Placebo | Placebo 1st Then Exenatide |
|---|---|---|
| Arm/Group Description | Study participants in period 1 will receive the study drug, exenatide, at a dose of 5mcg subcutaneously twice daily 30 minutes before meals for one month. During the second month of the study, the dose of exenatide will be increased to 10mcg subcutaneously twice daily before meals for one month. During the third month of the study, no study medication will be given and this will serve as a "wash out" period prior to the second period of the study (placebo). During the fourth and fifth months, study participants will get placebo alternatives to exenatide 5mcg and exenatide 10mcg, respectively, subcutaneously twice daily before meals. | Study participants in periods1 will receive the saline placebo at a dose of 5mcg subcutaneously twice daily 30 minutes before meals for one month. During the second month of the study, the dose of saline placebo will be increased to 10mcg subcutaneously twice daily before meals for one month. During the third month of the study, no treatment will be given and this will serve as a "wash out" period prior to the second periods of the study. During the fourth month participants will receive Exenatide 5mcg twice daily before meals. During the fifth month, study participants will get Exenatide 10mcg twice daily before meals. |
| Period Title: Low/High Dose of 1st Treatment (2months) | ||
| STARTED | 5 | 5 |
| COMPLETED | 3 | 4 |
| NOT COMPLETED | 2 | 1 |
| Period Title: Low/High Dose of 1st Treatment (2months) | ||
| STARTED | 3 | 4 |
| COMPLETED | 3 | 4 |
| NOT COMPLETED | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Placebo 1st Then Exenatide | Exenatide 1st Then Placebo | Total |
|---|---|---|---|
| Arm/Group Description | Study participants in period1 will receive the saline placebo at a dose of 5mcg subcutaneously twice daily 30 minutes before meals for one month. During the second month of the study, the dose of saline placebo will be increased to 10mcg subcutaneously twice daily before meals for one month. During the third month of the study, no treatment will be given and this will serve as a "wash out" period prior to the second periods of the study. During the fourth month participants will receive Exenatide 5mcg twice daily before meals. During the fifth month, study participants will get Exenatide 10mcg twice daily before meals. | Study participants in period 1 will receive the study drug, exenatide, at a dose of 5mcg subcutaneously twice daily 30 minutes before meals for one month. During the second month of the study, the dose of exenatide will be increased to 10mcg subcutaneously twice daily before meals for one month. During the third month of the study, no study medication will be given and this will serve as a "wash out" period prior to the second period of the study (placebo). During the fourth and fifth months, study participants will get placebo alternatives to exenatide 5mcg and exenatide 10mcg, respectively, subcutaneously twice daily before meals. | Total of all reporting groups |
| Overall Participants | 5 | 5 | 10 |
| Age (years) [Median (Standard Deviation) ] | |||
| Median (Standard Deviation) [years] |
61
(4.2)
|
61
(3.8)
|
61
(4.0)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
5
100%
|
5
100%
|
10
100%
|
| Male |
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
2
40%
|
2
40%
|
4
40%
|
| White |
3
60%
|
3
60%
|
6
60%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
5
100%
|
5
100%
|
10
100%
|
Outcome Measures
| Title | Determine Changes in Bone Resorption Markers During the Treatment With a GLP-1 Receptor Agonist (Exenatide) Compared to Placebo in Patients With T2DM. |
|---|---|
| Description | Bone reabsorption by bone-specific alkaline phosphatase (BAP) was assessed. Distribution of the Difference between EX/PBO Low/High Dose and Baseline Levels were calculated. |
| Time Frame | Baseline to 20 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| For Crossover study, participants were matched for the placebo and study drug arms. As such, only data from participants completing both arms were included in the statistical analysis. |
| Arm/Group Title | Exenatide 1st Then Placebo | Placebo 1st Then Exenatide |
|---|---|---|
| Arm/Group Description | Study participants in phase1 will receive the study drug, exenatide, at a dose of 5mcg subcutaneously twice daily 30 minutes before meals for one month. During the second month of the study, the dose of exenatide will be increased to 10mcg subcutaneously twice daily before meals for one month. During the third month of the study, no study medication will be given and this will serve as a "wash out" period prior to the second phase of the study (placebo). During the fourth and fifth months, study participants will get placebo alternatives to exenatide 5mcg and exenatide 10mcg, respectively, subcutaneously twice daily before meals. | Study participants in phase1 will receive the saline placebo at a dose of 5mcg subcutaneously twice daily 30 minutes before meals for one month. During the second month of the study, the dose of saline placebo will be increased to 10mcg subcutaneously twice daily before meals for one month. During the third month of the study, no treatment will be given and this will serve as a "wash out" period prior to the second phase of the study. During the fourth month participants will receive Exenatide 5mcg twice daily before meals. During the fifth month, study participants will get Exenatide 10mcg twice daily before meals. |
| Measure Participants | 3 | 4 |
| Mean (Standard Deviation) [mg/L] |
1.925
(1.6)
|
-0.20
(3.34)
|
| Title | Determine Changes in Bone Turnover Markers by Serum N-Telo Peptide During the Treatment With a GLP-1 Receptor Agonist (Exenatide) Compared to Placebo in Patients With T2DM. |
|---|---|
| Description | Bone turnover by Serum N-Telo peptide (NTX) was assessed. Distribution of the Difference between EX/PBO Low/High Dose and Baseline Levels were calculated |
| Time Frame | Baseline to 20 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| For Crossover, study, participants were matched for the placebo and study drug arms. As such, only data from participants completing both arms were included in the statistical analysis. |
| Arm/Group Title | Exenatide Then Placebo | Placebo Then Exenatide |
|---|---|---|
| Arm/Group Description | Study participants in phase1 will receive the study drug, exenatide, at a dose of 5mg subcutaneously twice daily 30 minutes before meals for one month. During the second month of the study, the dose of exenatide will be increased to 10mg subcutaneously twice daily before meals for one month. During the third month of the study, no study medication will be given and this will serve as a "wash out" period prior to the second phase of the study (placebo). During the fourth and fifth months, study participants will get placebo alternatives to exenatide 5mg and exenatide 10mg, respectively, subcutaneously twice daily before meals. exenatide: exenatide 5mcg sq twice daily for one month and exenatide 10mcg twice daily for month 2. The 3rd month is a washout period. Month 4 and 5 saline placebo is given as 5mcg and 10mcg respectively. | Study participants in phase1 will receive the saline placebo, at a dose of 5mcg subcutaneously twice daily 30 minutes before meals for one month. During the second month of the study, the saline placebo will be increased to 10mcg subcutaneously twice daily before meals for one month. During the third month of the study, no treatment will be given and this will serve as a "wash out" period prior to the second phase of the study. During the fourth month study participants will receive Exenatide 5mcg twice daily with meals. During the fifth month, study participants will receive exenatide 10mcg, subcutaneously twice daily before meals. exenatide: exenatide 5mcg sq twice daily for one month and exenatide 10mcg twice daily for month 2. The 3rd month is a washout period. Month 4 and 5 saline placebo is given as 5mcg and 10mcg respectively. |
| Measure Participants | 3 | 4 |
| Mean (Standard Deviation) [nMBCE/L] |
-0.8
(2.31)
|
1.725
(2.72)
|
| Title | Determine Changes in Bone Turnover Markers by Tartrate-Resistant Acid Phosphatase 5b (TRACP5b) During the Treatment With a GLP-1 Receptor Agonist (Exenatide) Compared to Placebo in Patients With T2DM. |
|---|---|
| Description | Bone turnover by Tartrate-Resistant Acid Phosphatase 5b (TRACP5b) was assessed. Distribution of the Difference between EX/PBO Low/High Dose and Baseline Levels were calculated. |
| Time Frame | Baseline to 20 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| For Crossover, study, participants were matched for the placebo and study drug arms. As such, only data from participants completing both arms were included in the statistical analysis. |
| Arm/Group Title | Exenatide 1st Then Placebo | Placebo 1st Then Exenatide |
|---|---|---|
| Arm/Group Description | Study participants in phase1 will receive the study drug, exenatide, at a dose of 5mcg subcutaneously twice daily 30 minutes before meals for one month. During the second month of the study, the dose of exenatide will be increased to 10mcg subcutaneously twice daily before meals for one month. During the third month of the study, no study medication will be given and this will serve as a "wash out" period prior to the second phase of the study (placebo). During the fourth and fifth months, study participants will get placebo alternatives to exenatide 5mcg and exenatide 10mcg, respectively, subcutaneously twice daily before meals. | Study participants in phase1 will receive the saline placebo at a dose of 5mcg subcutaneously twice daily 30 minutes before meals for one month. During the second month of the study, the dose of saline placebo will be increased to 10mcg subcutaneously twice daily before meals for one month. During the third month of the study, no treatment will be given and this will serve as a "wash out" period prior to the second phase of the study. During the fourth month participants will receive Exenatide 5mcg twice daily before meals. During the fifth month, study participants will get Exenatide 10mcg twice daily before meals. |
| Measure Participants | 3 | 4 |
| Mean (Standard Deviation) [U/L] |
0.05
(0.80)
|
0.325
(0.59)
|
Adverse Events
| Time Frame | Baseline to 20 weeks | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | clinicaltrials.gov definitions used | |||
| Arm/Group Title | Exenatide 1st Then Placebo | Placebo 1st Then Exenatide | ||
| Arm/Group Description | Study participants in phase1 will receive the study drug, exenatide, at a dose of 5mcg subcutaneously twice daily 30 minutes before meals for one month. During the second month of the study, the dose of exenatide will be increased to 10mcg subcutaneously twice daily before meals for one month. During the third month of the study, no study medication will be given and this will serve as a "wash out" period prior to the second phase of the study (placebo). During the fourth and fifth months, study participants will get placebo alternatives to exenatide 5mcg and exenatide 10mcg, respectively, subcutaneously twice daily before meals. | Study participants in phase1 will receive the saline placebo at a dose of 5mcg subcutaneously twice daily 30 minutes before meals for one month. During the second month of the study, the dose of saline placebo will be increased to 10mcg subcutaneously twice daily before meals for one month. During the third month of the study, no treatment will be given and this will serve as a "wash out" period prior to the second phase of the study. During the fourth month participants will receive Exenatide 5mcg twice daily before meals. During the fifth month, study participants will get Exenatide 10mcg twice daily before meals. | ||
All Cause Mortality |
||||
| Exenatide 1st Then Placebo | Placebo 1st Then Exenatide | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/3 (0%) | 0/4 (0%) | ||
Serious Adverse Events |
||||
| Exenatide 1st Then Placebo | Placebo 1st Then Exenatide | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/3 (0%) | 0/4 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Exenatide 1st Then Placebo | Placebo 1st Then Exenatide | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/3 (66.7%) | 0/4 (0%) | ||
| Gastrointestinal disorders | ||||
| Nausea/vomiting (1st treatment period) | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||
| Pruritis (2nd treatment period) | 1/3 (33.3%) | 1 | 0/4 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. Amy Warriner |
|---|---|
| Organization | UAB |
| Phone | 205-996-4004 |
| awarriner@uabmc.edu |
- F100929001