Januvia (Sitagliptin) in Healing Chronic Diabetic Foot Ulcers

Conditions:Podiatry, Diabetes, Diabetes, Diabetes, Diabetes
Therapuetic Areas:Endocrinology, Orthopedics / Podiatry
Age Range:18 - 80
Start Date:January 2014
End Date:March 2017
Contact:Paul J Kim, DPM

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Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy of Januvia (Sitagliptin) in Healing Chronic Diabetic Foot Ulcers

The primary objective of this study is to compare the rate of healing as well as percent of
wounds healed in Type II diabetic patients with chronic foot ulcerations receiving
sitagliptin versus placebo.

The hypothesis for this study is that subjects receiving daily doses of sitagliptin in
combination with their regular antihyperglycemic medications will result in increased
healing rates as well as a greater number of healed wounds as compared to subjects receiving
placebo and their regular antihyperglycemic medications.

Diabetes and diabetes related complications are a major cost burden on the healthcare system
encompassing 1/5 of the overall healthcare dollars in the United States [1]. Much of the
costs are related to the treatment of lower extremity wounds in the diabetic patient which
accounts for 60% of all nontraumatic amputations that are performed [2]. Amputation is
often preceded by a chronic ulceration. The incidence of diabetic ulcers is approximately
6% over a 3 year period [1]. Diabetic foot ulcerations are particularly challenging to heal
due to a host of factors including vascular compromise, peripheral neuropathy, and begin
prone to infection. Therefore, strategies to heal these wounds as quickly as possible are
of paramount importance.

Current strategies for chronic wound healing are limited to topical ointments/therapies,
allografts/xenografts with or without cell impregnation, dressings, and wound healing
devices. None of these current modalities have been shown to be clearly more effective than
another [3,4]. Currently, oral medications have not been examined for healing of these
chronic ulcerations. Particularly, antihyperglycemic medications have not been studied
specifically for the purpose of wound healing. Glucose control and wound healing have been
shown to be related [5-7]. However, it is thought that wound healing as a result of tighter
glucose control is merely a global effect rather than a direct result of the medications
utilized with no evidence that indicates that a specific antihyperglycemic medication works
better than another. Further, the mechanism of how and why this relationship exists is not
well understood. Specifically, how the microenvironment of the wound as evidenced by
changes in the biomarkers has not been delineated.

Januvia (sitagliptin) is an FDA approved antihyperglycemic drug that inhibits the enzyme
dipeptidyl peptidase 4 (DPP-4), which is an enzyme that is responsible for the breakdown of
glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). By
blocking this effect, GLP-1 and GIP stimulates the secretion of insulin and suppresses the
release of glucagon thereby normalizing blood glucose. The unique properties of this drug
decrease the likelihood of hypoglycemia. Therefore, this drug is often used in combination
of other antihyperglycemic medications to produce a synergistic effect.

DPP4 is expressed on the membranes of a variety of cell types as well as in soluble form,
and cleaves the two N-terminal amino acids, X-ala or X-pro, from a limited number of peptide
substrates, usually resulting in their inactivation. A family of DPP4 inhibitors, gliptins,
have been shown to preserve the full-length active forms of GLP1 and GIP in patients with
type II diabetes, enhancing antihyperglycemic activity. In addition to GLP1 and GIP,
important substrates of DPP4 essential for wound healing, and altered in diabetes, include
SDF-1α/β, PYY, NPY, GM-CSF, G-CSF, and IL3 [8-12]. SDF, PYY, and NPY are all important for
angiogenesis, while GM-CSF, G-CSF, and IL3 are necessary for leukocyte proliferation and
infiltration in the wound bed. The observation that DPP4 can cleave and inactive all of
these signaling molecules in vivo suggest that modulation of DPP4 activity will have a
direct effect on wound healing.

The prospect that a daily oral medication that improves overall glucose control of a
diabetic patient as well as expediting the wound healing process is profound. This study
explores this possibility.

This is a prospective, randomized study examining the ability of sitagliptin in expediting
the wound healing process in the diabetic patient with a chronic foot wound. This is a
single center study of 250 total subjects randomized into 2 arms. It is projected that this
study will take 3 years to complete. The two arms will be 1) Januvia (sitagliptin) 100mg q
day* and 2) placebo-control q day. Patients with Type II diabetes with a chronic foot ulcer
will be enrolled into this study. Each subject will be randomized into one of the two arms
and will participate in the study for a maximum of 16 weeks. At the end of 16 weeks
subjects will be exited from the study. If at any time during the course of the study the
wound heals, the subject will be exited from the study after a 2-week confirmatory visit.

*For moderate renal failure subjects, the sitagliptin dose will be adjusted to 50mg q day.

Inclusion Criteria:

- Male or female age >18

- Type II Diabetes with glycated hemoglobin (hemoglobin A1C) of < 11

- Currently on an oral hyperglycemic medication other than sitagliptin

- A chronic wound defined as the lack of wound healing progress of <15% per week or
50% over a month period

- Ankle brachial index of > 0.80

- Wound located on the foot or ankle (Wagner Grade 1,2)

- Able to comply with the requirements of the research trial

Exclusion Criteria:

- Current use of dipeptidyl-peptidase four (DPP-4) inhibitor or glucagon like peptide
one (GLP-1)agonist

- End stage renal disease

- Currently enrolled in another research trial that involves treatment of the wound

- Active infection of the wound

- Wound that probes to bone with osteomyelitis (Wagner Grade 3)
We found this trial at
Washington, District of Columbia 20007
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