Changes in Bone Turnover With Exposure to a GLP-1 Receptor Agonist

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.

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