Clinical trial NCT00732121: Bone Turnover in Type 2 Diabetes Patients
Official title: Effects of Sitagliptin On Markers of Bone Turnover in Patients With Type 2 Diabetes
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Type 2 Diabetes
Keywords: Type 2 Diabetes
Lead sponsor: University of Vermont
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2008-08-11
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: Background:

Incretin hormones are hormones produced by the gut in response to food intake. These hormones help the body to control the metabolism of glucose (sugar). In particular, two incretin hormones (GLP-1 and GIP) cause the pancreas to secrete more insulin in response to high blood glucose levels. This helps the body to metabolize the glucose more effectively, lowering blood sugar levels. In addition to their effects on the pancreas, GLP-1 and GIP have effects on other tissues, including the brain, gut, fat cells and bone. A new class of oral drugs developed for the treatment of type 2 diabetes mellitus (T2DM) called DPP-4 inhibitors increases levels of the active forms of GLP-1 and GIP in the body by preventing their breakdown. This study tests whether a medicine in this class called sitagliptin (Januvia), which is commonly used to treat T2DM, affects markers of bone turnover in patients with T2DM. The hypothesis is that treatment with sitagliptin will increase markers of bone formation and decrease markers of bone resorption during a mixed meal, by enhancing active circulating levels of GLP-1, GIP and GLP-2.

Methods:

To address this question we will recruit patients with T2DM whose diabetes is controlled with either diet+exercise or with metformin (another medicine commonly used to treat T2DM). Subjects will undergo measurement of body fat and bone mineral density by DEXA scanning and a 3-hour mixed meal test. During the mixed meal test blood samples will be taken to measure how much GLP-1 and GIP are produced. Markers of bone formation will also be measured in blood samples obtained during the mixed meal test. Subjects will then be randomly assigned to 8 weeks of treatment with either sitagliptin (100 mg/day) or matching placebo (an inactive tablet that does not contain medication). Subjects will be seen 4 weeks after commencing treatment to assess safety and tolerability. After 8 weeks of treatment the meal test will be repeated. Subjects will then be washed off of their initial treatment (sitagliptin or placebo) for 1 week (that is, they will receive no study medication during this period). After the washout period, they will commence a second 8-week period of treatment with the other study medication (that is, if they received sitagliptin initially, they will receive placebo during period 2 and vice-versa). At the end of period 2, subjects will undergo a third mixed meal test with measurement of GLP-1, GIP and markers of bone turnover.

Significance:

Recent studies suggest that oral antidiabetic medications of the thiazolidinedione class, such as rosiglitazone (Avandia) and pioglitazone (Actos), may weaken bones, increasing the risk of fractures in older women with diabetes. The proposed study will test whether drugs of the DPP-4 inhibitor class, such as sitagliptin (Januvia), have beneficial effects on bone turnover by increasing the activity of GLP-1 and GIP. Results of this pilot study may suggest the need to perform longer-term studies to determine whether DPP-4 inhibitors increase bone mineral density and reduce the risk of fractures in patients with diabetes.


Eligibility criteria: Inclusion Criteria:

* Type 2 diabetes treated with diet/exercise or metformin
* HbA1c less than or equal to 7%
* Men and women aged 45-80 years old
* If female, must be post-menopausal (natural or surgical)

Exclusion Criteria:

* Endocrine disorders (acromegaly, anorexia, Cushings, type 2 diabetes, hyperparathyroidism, hyperthyroidism, hypercalcemia)
* GI conditions (celiac sprue, gastric bypass/gastrectomy, active inflammatory bowel disease, cirrhosis)
* Cancer (including multiple myeloma) within 3 years of the study (except local non-melanoma skin cancers and cervical carcinoma in situ)
* Active alcoholism or drug abuse
* Chronic kidney disease with a GFR \< 60
* HIV/AIDS
* History of hypersensitivity reaction to sitagliptin or other DPP-4 inhibitors
* Hemoglobin \< 12 mg/dL for men and \< 10 for women
* Taking medications that could affect bone turnover (estrogen, progesterone, testosterone, bisphosphonates, SERMS, calcitonin, teriparatide cyclosporine glucocorticoids, methotrexate or phenothiazines), thiazolidinediones, sulfonylureas, dipeptidyl peptidase-4 inhibitors, exenatide, insulin, weight loss drugs

Primary outcomes:
measure: Change from baseline in the integrated response to the mixed meal test of markers of bone turnover following 8 weeks of treatment with sitagliptin vs. placebo.
timeFrame: 8 weeks per subject
Secondary outcomes:
measure: Change in the active GIP in response to the mixed meal test
timeFrame: 8 weeks
measure: Change in the active GLP-1 in response to the mixed meal test.
timeFrame: 8 weeks
measure: Change in the active GLP-2 in response to the mixed meal test.
timeFrame: 8 weeks
measure: Change in glucose response during the mixed meal test.
timeFrame: 8 weeks
measure: Change in insulin secretion during the mixed meal test.
timeFrame: 8 weeks
Other outcomes:
Locations:
city: South Burlington
country: United States
facility: University of Vermont
state: Vermont
Study officials:
affiliation: University of Vermont
name: Richard E Pratley, MD
role: PRINCIPAL_INVESTIGATOR
References: