Clinical trial NCT00420511: Beta-Cell Function and Sitagliptin Trial (BEST)
Official title: A Randomized Controlled Pilot Study Assessing the Effect of Sitagliptin on the Preservation of Beta-Cell Function in Patients With Type 2 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Type 2 Diabetes Mellitus
Keywords: Type 2 diabetes
beta-cell function
sitagliptin
intensive insulin therapy
Lead sponsor: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2007-01-11
Enrollment: 21
Sex: ALL
Minimum age (years): 30
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Preservation of Beta-cell Function Measured by Area-under-the-curve (C-peptide/Glucose)/HOMA-IR
timeFrame: 48 weeks
Secondary outcomes:
measure: Insulinogenic Index Divided by HOMA-IR at 48 Weeks
timeFrame: 48 weeks
measure: Fasting Blood Glucose at 48 Weeks
timeFrame: 48 weeks
measure: Area-under-the-glucose-curve (AUCglucose) on Meal Test at 1 Year
timeFrame: 1 year
measure: Time to Loss of Glycemic Control
timeFrame: 1 year
measure: Proportion of Patients Achieving Sustained Normoglycemia Off Medication at 1-week Post-insulin Therapy
timeFrame: 1 year
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Leadership Sinai Centre for Diabetes
state: Ontario
Study officials:
affiliation: Leadership Sinai Centre for Diabetes, University of Toronto
name: Bernard Zinman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leadership Sinai Centre for Diabetes, University of Toronto
name: Ravi Retnakaran, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Stein CM, Kramer CK, Zinman B, Choi H, Opsteen C, Retnakaran R. Clinical predictors and time course of the improvement in beta-cell function with short-term intensive insulin therapy in patients with Type 2 diabetes. Diabet Med. 2015 May;32(5):645-52. doi: 10.1111/dme.12671. Epub 2015 Jan 7.