Beta-Cell Function and Sitagliptin Trial (BEST) (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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Sitagliptin; Drug: metformin; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T 3L9
      • Leadership Sinai Centre for Diabetes

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Bernard Zinman, MD, Leadership Sinai Centre for Diabetes, University of Toronto; Principal Investigator: Ravi Retnakaran, MD, Leadership Sinai Centre for Diabetes, University of Toronto

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (Actual): September 1, 2009
• Study Completion (Actual): September 1, 2009

Study Registration Dates

• First Submitted: January 10, 2007
• First Submitted That Met QC Criteria: January 10, 2007
• First Posted (Estimate): January 11, 2007

Study Record Updates

• Last Update Posted (Estimate): January 2, 2012
• Last Update Submitted That Met QC Criteria: December 28, 2011
• Last Verified: December 1, 2011

More Information

Terms related to this study

• Keywords: Type 2 diabetes; intensive insulin therapy; sitagliptin; beta-cell function
• 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; Metformin; Sitagliptin Phosphate
• Other Study ID Numbers: 065-00