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

Condition(s) targeted: Diabetes Mellitus, Type 2

Intervention: Metformin or placebo (Drug); Repaglinide or placebo (Drug)

Phase: Phase 4

Status: Completed

Sponsored by: Steno Diabetes Center

Official(s) and/or principal investigator(s):
Allan A Vaag, M. D., Chief Physician, Study Chair, Affiliation: Steno Diabetes Center
Soeren S Lund, M. D., Principal Investigator, Affiliation: Steno Diabetes Center

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.

Official title: 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

Study design: Treatment, Randomized, Double-Blind, Active Control, Crossover Assignment, Efficacy Study

Primary outcome: HaemoglobinA1c

Secondary outcome:

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, lipoproten 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 acitivity.

DNA for genotyping.

Adverse events and safety variables (e.g. hypoglycaemia, haemoglobin, white blood cell count, cobalamine and folate).

Minimum age: 40 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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.

Steno Diabetes Center, Gentofte 2820, Denmark

Starting date: March 2001
Ending date: March 2003
Last updated: September 26, 2006