Effect of Insulin Glulisine vs Regular Human Insulin on Postprandial Endothelial Function in Type 2 Diabetes

Phase III b Indication Type 2 Diabetes Trial Objectives 1) Primary objective: The primary objective of the study is to evaluate the postprandial time course of nitrotyrosine after injection of insulin glulisine compared with regular human insulin. 2) Secondary objectives: The secondary objectives are to evaluate the postprandial time course of blood glucose, insulin, intact proinsulin, asymmetric dimethylarginine (ADMA), metal matrix proteasis (MMP-9), free fatty acids (FFA), oxidised LDL (ox-LDL), oxidative status (per ox), IL-18 as well as postprandial time course of microvascular blood circulation measured with laserdopplerflux at 37 °C (LDF37) and 44 C (LDF44).

Efficacy Variables Primary efficacy variablePostprandial time course of nitrotyrosineSecondary efficacy variablePostprandial time course of glucose, insulin, intact proinsulin, ADMA, MMP-9, FFA, ox-LDL, per-ox, and IL-18 as well as postprandial time course of laserdopplerflux at 37 °C and 44 °C Safety Variables Incidence and frequency of adverse events and evaluation of safety laboratory parameters Medication/Dosage Insulin glulisine, dose 0.10 U/kg and Regular Human Insulin, dose 0.10 U/kg Study Duration Duration of study participation for one patient: 5 - 43 days Overall duration of the study: 6 months Design Single-centre, open label, randomized, 2-way-crossover trial Population Male and female type 2 diabetic patients between 40 and 70 years with HbA1c between 6.5 % and 9.9 % and treated with sulfonyurea alone or in combination with Metformin in a stable dosage within the last 3 months Sample Size N = 15

Inclusion criteria

• Type 2 Diabetes mellitus according to the ADA criteria
• HbA1c between 6.5 % and 9.9 %
• Monotherapy with sulfonylurea or combined with Metformin in a stable dosage within the last 3 months
• Age between 40 and 70 years
• BMI < 40

Exclusion criteria

• Type 1 Diabetes mellitus
• Pre-Treatment with insulin within the last 6 months prior to screening
• Treatment with glitazones within the last 6 months prior to screening
• Pre-Treatment with PPARy-agonists, glinides or glucosidase inhibitors within the last 4 weeks prior to screening
• Untreated hypertension stage II-III according to WHO criteria
• Planned or anticipated change in antidiabetic and/or concomitant medication during study participation
• Total Cholesterol > 300 mg/dl (anamnestically)
• Hypokalemia (K < 3.5 mmol /l)
• Major micro- or macrovascular complications as judged by the investigator
• Tobacco use within the last 12 months prior to screening
• Drugs with major impact on endothelial function like nitrates etc.
• History of drug or alcohol abuse within the last five years prior to screening
• Anamnestic history of hypersensitivity to the study drugs or to drugs with similar chemical structures
• History of severe or multiple allergies
• Treatment with any other investigational drug within 3 months prior to screening
• Progressive fatal disease
• History of significant cardiovascular, respiratory, gastrointestinal, hepatic (ALAT and/or ASAT > 3 times the normal reference range), renal (creatinine > 1.1 mg/dL in women, > 1.5 mg/dL in men), neurological, psychiatric and/or haematological disease as judged by the investigator
• Pregnancy or breast feeding
• Sexually active women of childbearing potential not consistently and correctly practicing birth control by implants, injectables, combined oral contraceptives, hormonal intrauterine devices (IUDs), sexual abstinence or vasectomised partner
• Lack of compliance or other similar reason, that according to investigator, precludes satisfactory participation in the study