Beta-Cell Function and Sitagliptin Trial (BEST)

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Sitagliptin
* Drug: Placebo
* Drug: metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women between the ages of 30 and 75 inclusive Physician-diagnosed type 2 diabetes on 0-2 oral hypoglycemic agents Negative for anti-glutamic acid decarboxylase (anti-GAD_ antibodies (to rule out Latent Autoimmune Diabetes of Adults (LADA) 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: Current insulin therapy Type 1 diabetes or secondary forms of diabetes Any major illness with a life expectancy of < 5 years or that may interfere with the patient's participation in the study Involvement in any other study requiring drug therapy 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) 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 Excessive alcohol consumption, defined as > 14 alcoholic drinks per week for males and > 9 alcoholic drinks per week for females 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 History of serious arrhythmia or atrioventricular block on baseline electrocardiogram Uncontrolled hypertension (systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg) Unwillingness to undergo multiple daily insulin injection therapy for 4 weeks Unwillingness to perform capillary blood glucose monitoring at least 4 times per day during intensive insulin therapy

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sitagliptin<br>Sitagliptin 100mg once a day (od) by mouth (po) | Drug: Sitagliptin<br>* sitagliptin 100 mg once a day<br>* Other names: januvia;Drug: metformin<br>* metformin 1000 mg twice a day (bid) by mouth (po)<br>* Other names: glucophage;|
| Placebo Comparator: Placebo arm<br>Placebo once a day (od) by mouth (po) | Drug: Placebo<br>* placebo once a day<br>Drug: metformin<br>* metformin 1000 mg twice a day (bid) by mouth (po)<br>* Other names: glucophage;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preservation of Beta-cell Function Measured by Area-under-the-curve (C-peptide/Glucose)/HOMA-IR | Area-under-the-C-peptide-curve (AUCCpep) and area-under-the-glucose-curve (AUCgluc) from 0 to 240 minutes during meal tests were calculated using the trapezoidal rule. Insulin resistance was assessed using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). Beta-cell function was assessed using the ratio of total AUCCpep to AUCgluc divided by HOMA-IR (AUCCpep/gluc/HOMA-IR), a measure of insulin secretion in the context of ambient insulin sensitivity, analogous to the disposition index and adaptation index. Higher AUCCpep/gluc/HOMA-IR is indicative of better beta-cell function. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulinogenic Index Divided by HOMA-IR at 48 Weeks | Insulinogenic index was calculated as the incremental change in insulin from 0 to 30 minutes divided by the incremental change in glucose over the same period of time. Insulinogenic index divided by HOMA-IR provides an additional measure of beta-cell function. A higher value indicates better beta-cell function | 48 weeks | 
| Fasting Blood Glucose at 48 Weeks |  | 48 weeks | 
| Area-under-the-glucose-curve (AUCglucose) on Meal Test at 1 Year |  | 1 year | 
| Time to Loss of Glycemic Control |  | 1 year | 
| Proportion of Patients Achieving Sustained Normoglycemia Off Medication at 1-week Post-insulin Therapy |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes, beta-cell function, sitagliptin, intensive insulin therapy