DPP4-Inhibitors and Bone Metabolism in Diabetes

This study is a superiority, double-blinded, randomized, placebo-controlled clinical trial designed to investigate the safety and efficacy of 52-week sitagliptin 100 mg therapy in improving bone outcomes in women affected by type 2 diabetes.

In particular, the primary objective of this study is:

To test the superiority of sitagliptin 100 mg in addition to metformin versus placebo with metformin in improving bone mineral density from baseline to the end of treatment (week 52), as estimated by DXA on the lumbar spine and femoral neck.

Secondary endpoints are:

Evaluation of the association between circulating DPP4 activity and serum markers of bone metabolism at baseline and after 24- and 52-week sitagliptin supplementation.

Determination of whether circulating DPP4 activity is associated with impaired vitamin D availability and whether chronic DPP4 inhibition induces changes in serum vitamin D levels after treatment.

Examination of the relationship between DPP4 activity and systemic markers of inflammation, which are closely related to impaired glucose metabolism, at baseline and after 24- and 52-week sitagliptin supplementation.

Inclusion criteria

• Female subjects ≥ 18 years
• Diagnosis of Type 2 Diabetes according to American Diabetes Association 2009 criteria
• Body mass index (BMI) between 20-40 kg/m2
• Body weight ≤ 120 kg (due to limitations imposed by DXA equipment);
• HbA1c < 7.5%
• Treatment with metformin in monotherapy at a stable dose for ≥12 weeks prior to enrolment
• Women not of childbearing potential may participate and include those who are:

I) infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal ligation), congenital anomaly such as Mullerian agenisis; or II) postmenopausal - defined as either

• A woman 50 to 54 years of age (inclusive) with an intact uterus, not hormone therapy who has had either

• cessation of menses for at least 1 years or
• at least 6 months of spontaneous amenorrhea with a follicle-stimulating hormone > 40 mIU/mL; or
• a woman 55 or holder not on hormone therapy, who has had at least 6 months of spontaneous amenorrhea; or
• a woman at least 55 years of age with a diagnosis of menopause prior to starting hormone replacement therapy - Women of childbearing potential participating: I) cannot be pregnant or intend to become pregnant II) cannot be breastfeeding III) must remain abstinent or use 1 highly effective method of contraception or combination of 2 effective methods of contraception for the entirety of the study IV) test negative for pregnancy at the time of screening

Exclusion criteria

• Treatments known to significantly influence bone metabolism (e.g. bisphosphonates, calcitonin, corticosteroids or hormone replacement therapy)
• Osteomalacia
• Paget.s disease
• Hyperparathyroidism
• Hyperthyroidism
• Chronic liver failure/cirrhosis
• Kidney failure
• Current or history of therapy with antidiabetic agents other than metformin
• Pregnancy/lactation, childbearing potential women who do not give their consent to remain abstinent or use 1 highly effective method of contraception or combination of 2 effective methods of contraception for the entirety of the study
• Pregnancy/lactation
• Substance abuse, clinically significant depression or current psychiatric care
• Refuse or are unable to give informed consent to participate in the study Subjects taking vitamin D and/or calcium supplements at enrolment will be instructed to continue this therapy keeping the doses unchanged throughout the entire study.