Beta Cell Relieving and Cardiovascular Protective Effects of LANTUS Treatment in Type 2 Diabetes Patients
The purpose of this phase IV clinical trial is to investigate the effect of Insulin glargine + metformin treatment vs. sulfonylurea + metformin treatment vs. DPP-4 + metformin treatment vs. healthy volunteers on ß-cell function after the uptake of a standardized meal.
|Study Design:||Observational Model: Case Control
Time Perspective: Prospective
|Official Title:||Beta Cell Relieving and Cardiovascular Protective Effects of LANTUS Treatment in Type 2 Diabetes Patients - Investigation on Postprandial Excursions of Proinsulin and PAI-1 Levels|
- Investigation of ß-cell function via comparison of AUC0-300 minutes of intact Proinsulin in T2DM patients treated with LANTUS + Metformin (MET) vs. T2DM patients treated with Sulfonylurea (SU) + Metformin [ Time Frame: 0-300 minutes after standardized meal ] [ Designated as safety issue: No ]Comparison of AUC0-300 min [intact Proinsulin] between T2DM patients treated with LANTUS + Metformin and T2DM patients treated with Sulfonylurea + MET after uptake of standardized meal
- Investigation of insulin, intact proinsulin, glucose and PAI-1 levels over a 5 h period after uptake of a standardized meal comparing four different population groups [ Time Frame: 0-300 minutes after standardized meal ] [ Designated as safety issue: No ]
Comparison of the AUC0-300 of intact proinsulin between each of the 4 treatment groups with the exception of T2DM patients treated with LANTUS + MET and T2DM patients treated with SU + MET after uptake of a standardized meal.
Comparison of the AUC0-300 for insulin, the AUC0-300 and the AUC0-180 for blood glucose, the mean maximum levels of intact proinsulin, insulin and BG, and the PAI-1 level excursion at the time points 0, 150 and 300 min between each of the 4 treatment groups.
Comparison of the change in the insulin/intact proinsulin ratio between each of the 4 treatment groups
|Study Start Date:||November 2009|
|Study Completion Date:||July 2010|
|Primary Completion Date:||July 2010 (Final data collection date for primary outcome measure)|
T2DM patients treated with LANTUS + MET
T2DM patients treated with LANTUS + Metformin(MET) in their routine antidiabetic therapy. These patients do not receive any study specific medication.
T2DM patients treated with SU + MET
T2DM patients treated with Sulfonylurea (SU) + Metformin(MET)in their routine antidiabetic therapy. These patients do not receive any study specific medication.
T2DM patients treated with DPP-4 + MET
T2DM patients treated with Dipeptidylpeptidase 4 inhibitors (DPP-4) + Metformin(MET) in their routine antidiabetic therapy. These patients do not receive any study specific medication.
healthy volunteres who do not receive any antidiabetic medication in their routine therapie.
Type 2 diabetes mellitus is a progressive disease characterised by a steady loss of beta cell function and an increase in the proinsulin/insulin ratio. During the recent years intact proinsulin has been the topic of interest in numerous preclinical and clinical studies in patients with type 2 diabetes mellitus. Intact proinsulin was confirmed as a marker of functional beta cell failure and as a predictor of increased beta cell loss due to apoptosis and/or diminished neogenesis.
A number of population based studies showed that intact proinsulin is a strong predictor of coronary heart disease in diabetic, and in non-diabetic patients. In a clinical trial investigating human proinsulin as a therapeutic approach for the treatment of diabetes mellitus an eight fold increase in CVD was found during treatment with human proinsulin compared to human regular insulin, indicating a thrombo-embolic potential of intact proinsulin. In a recent investigation an association could be confirmed between increased proinsulin plasma concentrations and the severity of angiographical characterised CHD.
Even the exact mechanism how proinsulin is involved in the pathogenesis of atherosclerosis is not completely recognized, it was already shown that PAI-1 activity increases after proinsulin administration in vitro, and there is increasing evidence that the atherogenic effects of proinsulin might be linked to increasing plasminogen activator inhibitor-1 (PAI-1) levels with subsequent inhibition of fibrinolysis and an augmented thrombogenic potency.
Treatment with sulfonylurea increases intact proinsulin secretion, and in a couple of studies, sulfonylurea treatment was found to be associated with an increased cardiovascular risk. In contrast, several studies have shown that after the introduction of insulin treatment in type 2 diabetic patients intact proinsulin levels and plasma PAI 1 levels decline, indicating not only beta cell protection, but also antiatherogenic properties of insulin. In a recent study, we have shown that treatment with basal insulin in combination with metformin effectively reduces intact proinsulin levels, and that insulin glargine is superior to NPH insulin in controlling postprandial release of intact proinsulin over an entire day.
Recently a new therapeutic concept using DPP IV inhibitors in combination with metformin has been introduced in the treatment of type 2 diabetic patients. There is some evidence that, in the beta cell, DPP IV Inhibitors might improve the conversion of intact Proinsulin into Insulin and C-peptide and thereby reduce circulating intact proinsulin levels. Since the number of type 2 diabetic patients treated with DPP-IV inhibitors is steadily increasing, there is a need to generate more data on the postprandial release of intact proinsulin in patients treated with DPP-IV inhibitors compared to Insulin or sulfonylurea treatment.
The rationale of the study is to investigate the effect of glargine and metformin treatment compared to sulfonylurea and metformin treatment and compared to DPP-4 inhibitor and metformin treatment on postprandial intact proinsulin release and postprandial PAI-1 levels. Accompanying a comparison of postprandial intact proinsulin release and the time course of postprandial PAI-levels in between all three antidiabetic treatment groups and a non-diabetic control group will be performed as well.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01206712
|IKFE Institute for Clinical Research and Development|
|Mainz, Germany, 55116|
|Principal Investigator:||Thomas Forst, Prof. MD||IKFE Institute for Clinical Research and Development|