Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 diabetes, sitagliptin, Januvia
Brief summary
The purpose of this study is to determine if the use of sitagliptin increases bone formation and reduces bone turnover in postmenopausal women with type 2 diabetes.
Detailed description
Patients with Type 2 Diabetes Mellitus (T2DM) are at an increased risk of fracture, despite having bone mineral density (BMD) 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, incretins have been a therapeutic target for the treatment of T2DM through GLP-1 receptor analogs or inhibition of incretin metabolism via dipeptidyl peptidase 4 (DPP-4) inhibitors (i.e. sitagliptin). Inhibition of DPP-4 leads to an approximate doubling of GLP-1 and GIP levels but also leads to reduced breakdown of GLP-2. Less is known about the effect of incretin-directed therapies, specifically sitagliptin, and bone metabolism. To our knowledge, two studies have looked at the direct effects of currently available incretin-directed therapies on bone metabolism. Exenatide (a GLP-1 analog) treatment of insulin resistant and type 2 diabetic rats resulted in osteogenic effects with increased osteocalcin levels following treatment. In a study of female non-diabetic Sprague-Dawley rats treated with pioglitazone, rosiglitazone, sitagliptin, vs. placebo, no significant change in bone mineral density was seen in the sitagliptin or placebo treated rats (compared to significant loss of bone mineral density in the TZD groups). Even fewer published studies are available evaluating changes in bone metabolism with the use of incretin hormones in humans. The majority of the human studies have been completed with GLP-2. These studies show a dose-dependent effect of GLP-2 on bone resorption and, preliminarily, show improved bone mineral density in postmenopausal women treated with GLP-2. However, the changes in incretin activity vary in persons with glucose intolerance and T2DM. Therefore, it is important to understand the potential effects of these medications on bone metabolism in persons prescribed these medications for treatment of their T2DM.
Interventions
DRUGsitagliptin
sitagliptin 100mg daily
OTHERPlacebo
1 pill daily
Sponsors
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
45 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Postmenopausal women (as defined by age \>55 years old or amenorrhea for \>1years) * 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. * Hemoglobin A1c (HbA1c) of 6.5-9.0%
Exclusion criteria
* Use of an incretin mimetic (i.e. exenatide), 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bone Turnover in Subjects Treated With Sitagliptin When Compared to Those Treated With Placebo. | 8 weeks | Bone turnover assessed using change in TRACP5b over 8 weeks of treatment. |
| Bone Turnover in Subjects Treated With Sitagliptin When Compared to Those Treated With Placebo | 8 WEEKS | Bone turnover assessed using change in bone-specific alkaline phosphatase (BAP) over 8 weeks of treatment. |
Countries
United States
Participant flow
Recruitment details
Postmenopausal women with diabetes mellitus on no medications or metformin treatment alone were recruited from an outpatient clinic setting.
Pre-assignment details
Potential participants completed a screening visit to ensure all study inclusion criteria were met. If on metformin at the screening visit, the metformin was discontinued. Potential participants presented 1 month later for the baseline visit and for randomization.
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin Sitagliptin
sitagliptin: sitagliptin 100mg daily | 2 |
| Placebo Placebo
Placebo: 1 pill daily | 3 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lab unable to analyze BTM | 0 | 2 |
Baseline characteristics
| Characteristic | Sitagliptin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 57.5 years STANDARD_DEVIATION 6.5 | 61.0 years STANDARD_DEVIATION 8.3 | 61.0 years STANDARD_DEVIATION 8.6 |
| Diastolic Blood Pressure | 82 mmHg STANDARD_DEVIATION 8 | 78 mmHg STANDARD_DEVIATION 6.2 | 78 mmHg STANDARD_DEVIATION 7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 2 participants | 3 participants | 5 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Systolic Blood Pressure | 119 mmHg STANDARD_DEVIATION 11 | 130 mmHg STANDARD_DEVIATION 10 | 130 mmHg STANDARD_DEVIATION 12.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 3 |
| other Total, other adverse events | 0 / 2 | 0 / 3 |
| serious Total, serious adverse events | 0 / 2 | 0 / 3 |
Outcome results
Primary
Bone Turnover in Subjects Treated With Sitagliptin When Compared to Those Treated With Placebo
Bone turnover assessed using change in bone-specific alkaline phosphatase (BAP) over 8 weeks of treatment.
Time frame: 8 WEEKS
Population: The difference between the bone turnover markers bone alkaline phosphatase (BAP) from baseline to end of study were calculated for treatment and placebo groups. Serum samples were not available for one placebo participant at baseline and for one placebo patient at end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Bone Turnover in Subjects Treated With Sitagliptin When Compared to Those Treated With Placebo | 0.05 mg/L | Standard Deviation 1.34 |
| Placebo | Bone Turnover in Subjects Treated With Sitagliptin When Compared to Those Treated With Placebo | 0 mg/L | Standard Deviation 0 |
Primary
Bone Turnover in Subjects Treated With Sitagliptin When Compared to Those Treated With Placebo.
Bone turnover assessed using change in TRACP5b over 8 weeks of treatment.
Time frame: 8 weeks
Population: The difference between the bone turnover markers TRACP5b from baseline to end of study were calculated for treatment and placebo groups. Serum samples were not available for one placebo participant at baseline and for one placebo patient at end of study. As a result we were unable to analyze the 2 participants with missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Bone Turnover in Subjects Treated With Sitagliptin When Compared to Those Treated With Placebo. | -0.25 U/L | Standard Deviation 0.07 |
| Placebo | Bone Turnover in Subjects Treated With Sitagliptin When Compared to Those Treated With Placebo. | 0.30 U/L | Standard Deviation 0 |