Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet

Effect of Metformin Versus Repaglinide Treatment on Glycemic Control and Non-Glycaemic Cardiovascular Risk Factors in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet

Background: Metformin is the first drug of choice in obese patients with type-2 diabetes (T2DM) due to its antiglycaemic as well as its cardiovascular protective potentials. In non-obese T2DM patients insulin-secretagogues are empirically used as first choice. The aim of this study was to evaluate the effect of metformin versus an insulin-secretagogue, repaglinide on glycaemic regulation and non-glycaemic cardiovascular risk markers in non-obese patients with T2DM.

Methods: Single-center, randomised, double-masked, double-dummy, cross-over-study of 96 non-obese (BMI ≤ 27 kg/m2) Caucasian T2DM-patients. After a one month run-in on diet-only treatment, patients were randomised to either repaglinide 2mg three times a day (t.i.d). followed by metformin 1g twice a day (b.i.d.) or vice versa each for a period of four months with a one month wash-out between interventions.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Metformin; Drug: Placebo-Repaglinide.; Drug: Repaglinide; Drug: Placebo-Metformin.; Other: Diet-only.

• Study Type: Interventional
• Enrollment: 100
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Gentofte, Denmark, 2820
    • Steno Diabetes center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Type-2 diabetes, defined as:

• Age at onset of diabetes ≥ 40 years
• Fasting serum C-peptide ≥ 300 pmol/l or a non-fasting or glucagon-stimulated serum C-peptide ≥ 600 pmol/l
• No history of ketonuria or ketoacidosis.
• BMI ≤ 27 kg/m2.
• Fasting plasma-glucose ≥ 6.5 mmol/l after at least one month of diet-only treatment.
• HbA1c ≤ 9.5% at ongoing oral anti-hyperglycaemic agents. HbA1c ≥ 6.5% after minimum one month of diet-only treatment.
• Weight-loss of no more than 5.0 kg during the last 6 months prior to enrolment.

Exclusion Criteria:

• Type-1 diabetes
• Insulin-treated type-2 diabetes
• Secondary diabetes, heart-failure
• Serum-creatinine above the upper limit
• Serum-ASAT elevated more than 3 fold above the upper limit
• Factor II-VII-X decreased below 0.7
• Ongoing coexisting illnesses with a life-shortening prognosis
• Mental retardation or reduced intellectual behaviour
• Pregnancy
• History of drug-abuse or HbA1c>10.5% at two separate visits with at least one month interval during treatment-periods.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 4; Metformin plus placebo-Repgalinide. Double-masked, randomized. Duration: Four months.	Drug: Metformin; Tablet Metformin 500 mg; Dosage: 1000 mg two times daily. Duration: Four months.; Drug: Placebo-Repaglinide.; Tablet Placebo (corresponding to 1 mg Repaglinide). Dosage: 2 tablets three times daily. Duration: Four months.
ACTIVE_COMPARATOR: 2; Repaglinide plus Placebo-Metformin. Double-masked, randomized. Duration: Four months.	Drug: Repaglinide; Tablet Repaglinide 1 mg; Dosage: 2 mg three times daily. Duration: Four months.; Drug: Placebo-Metformin.; Tablet Placebo (corresponding to 500 mg Metformin). Dosage: 2 tablets two times daily. Duration: Four months.
OTHER: 1; Run-in period: Treatment: Diet-only. Duration: One month.	Other: Diet-only.; Diet-only treatment. Duration: One month.
OTHER: 3; Wash-out period: Treatment: Diet-only: Duration: One month.	Other: Diet-only.; Diet-only treatment. Duration: One month.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
HaemoglobinA1c

Secondary Outcome Measures

Outcome Measure
Home-monitored 7-point plasma-glucose profiles
Body-weight
Waist- and hip-circumference
Fasting and postprandial (after a standard test-meal) measures of plasma-glucose, insulin, c-peptide, free fatty acids, lipoproteins, triglycerides and other markers related to lipid-metabolism (e.g. apo-lipoproteins, lipoprotein particle size etc.).
Biomarkers related to inflammation, endothelial dysfunction and fibrinolysis (e.g. hs-CRP, TNF-alpha, IL-6, ICAM, VCAM, E-selectin, vWF, PAI-1 and t-PA, adiponectin, ADMA, AGE-peptides).
Albuminuria and 24-hour blood-pressure measurements.
Platelet aggregation, markers of platelet activity and fibrinolytic markers fasting as well as before and after physical activity.
DNA for genotyping.
Adverse events and safety variables (e.g. hypoglycaemia, haemoglobin, white blood cell count, cobalamine and folate).

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Investigators: Study Chair: Allan A Vaag, M. D., Chief Physician, Steno Diabetes Center Copenhagen

Study record dates

Study Major Dates

• Study Start: March 1, 2001
• Study Completion: March 1, 2003

Study Registration Dates

• First Submitted: July 1, 2005
• First Submitted That Met QC Criteria: July 1, 2005
• First Posted (ESTIMATE): July 12, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): December 8, 2008
• Last Update Submitted That Met QC Criteria: December 5, 2008
• Last Verified: December 1, 2008

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin; Repaglinide
• Other Study ID Numbers: ReMet