Bone Turnover in Type 2 Diabetes Patients

Effects of Sitagliptin On Markers of Bone Turnover in Patients With Type 2 Diabetes

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.

Study Overview

• Status: Unknown
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Placebo; Drug: Sitagliptin

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Vermont
    • South Burlington, Vermont, United States, 05403
      • University of Vermont

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; Sitagliptin	Drug: Sitagliptin; 100 mg daily for 4 weeks; Other Names: Januvia (brand name for sitagliptin)
Placebo Comparator: 2; Placebo arm	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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.	8 weeks per subject

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in the active GIP in response to the mixed meal test	8 weeks
Change in the active GLP-1 in response to the mixed meal test.	8 weeks
Change in the active GLP-2 in response to the mixed meal test.	8 weeks
Change in glucose response during the mixed meal test.	8 weeks
Change in insulin secretion during the mixed meal test.	8 weeks

Collaborators and Investigators

• Sponsor: University of Vermont
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Richard E Pratley, MD, University of Vermont

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (Anticipated): June 1, 2010
• Study Completion (Anticipated): August 1, 2010

Study Registration Dates

• First Submitted: August 7, 2008
• First Submitted That Met QC Criteria: August 7, 2008
• First Posted (Estimate): August 11, 2008

Study Record Updates

• Last Update Posted (Estimate): June 28, 2010
• Last Update Submitted That Met QC Criteria: June 25, 2010
• Last Verified: February 1, 2009

More Information

Terms related to this study

• Keywords: Type 2 Diabetes
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Sitagliptin Phosphate
• Other Study ID Numbers: Merck-33283