Beta-Cell Function and Sitagliptin Trial (BEST)

A Randomized Controlled Pilot Study Assessing the Effect of Sitagliptin on the Preservation of Beta-Cell Function in Patients With Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by progressive deterioration in the function of the pancreatic beta-cells, which are the cells that produce and secrete insulin (the hormone primarily responsible for the handling of glucose in the body). The investigators propose a double-blind, randomized controlled pilot study comparing the effect of sitagliptin (a novel anti-diabetic drug with beta-cell protective potential) versus placebo, on the preservation of beta-cell function over one year in patients with T2DM on metformin, the first-line agent for the treatment of T2DM (ie. the study groups will be (i) sitagliptin and metformin versus (ii) placebo and metformin). This study may demonstrate an important beta-cell protective capacity of sitagliptin.

Hypothesis: In patients with T2DM on metformin, treatment with the DPP-IV inhibitor sitagliptin will preserve pancreatic beta-cell function.

Medications currently used in the treatment of T2DM have not been shown to modify the progressive decline in beta-cell function that occurs over time. Recent evidence, however, suggests that a new class of anti-diabetic medications, called dipeptidyl peptidase-IV (DPP-IV) inhibitors, may be able to protect beta cells and hence alter the natural history of T2DM. We thus wish to study the effect of sitagliptin (a DPP-IV inhibitor) on the preservation of beta-cell function in patients with T2DM randomized to either (i) sitagliptin and metformin or (ii) placebo and metformin.

Inclusion Criteria:

1. Men and women between the ages of 30 and 75 inclusive
2. Physician-diagnosed type 2 diabetes on 0-2 oral hypoglycemic agents
3. Negative for anti-glutamic acid decarboxylase (anti-GAD_ antibodies (to rule out Latent Autoimmune Diabetes of Adults (LADA)
4. A1c at screening between 6.5% and 9% inclusive if on no oral hypoglycemic agents or 6.0% and 9.0% inclusive if on 1-2 oral hypoglycemic agents

Exclusion Criteria:

1. Current insulin therapy
2. Type 1 diabetes or secondary forms of diabetes
3. Any major illness with a life expectancy of < 5 years or that may interfere with the patient's participation in the study
4. Involvement in any other study requiring drug therapy
5. Renal dysfunction as evidenced by serum creatinine >/= 136 umol/L for males or >/= 124 umol/L for females or abnormal creatinine clearance (< 60 ml/min by Modification of Diet in Renal Disease (MDRD) formula)
6. Hepatic disease considered to be clinically significant (includes jaundice, chronic hepatitis, or previous liver transplant) or transaminases > 2.5 times the upper limit of normal
7. Excessive alcohol consumption, defined as > 14 alcoholic drinks per week for males and > 9 alcoholic drinks per week for females
8. Pregnancy or unwillingness to use reliable contraception. Women should not be planning pregnancy for the duration of the study. Reliable contraception includes: birth control pill, intra-uterine device, abstinence, tubal ligation, partner vasectomy, or condoms with spermicide. Any women who miss a menstrual period or think that they may be pregnant must have a pregnancy test as soon as possible
9. History of serious arrhythmia or atrioventricular block on baseline electrocardiogram
10. Uncontrolled hypertension (systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg)
11. Unwillingness to undergo multiple daily insulin injection therapy for 4 weeks
12. Unwillingness to perform capillary blood glucose monitoring at least 4 times per day during intensive insulin therapy