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.