Feasibility of Once/Daily Administered GLP/1 Receptoragonist (Lixisenatide) in Combination With Basal Insulin

Study Overview
=================
Brief Summary
-----------------
Premixed insulin-based therapy is a standard insulin treatment strategy in Austria. The widespread use of premixed insulin is explained by high acceptance by health care professionals and patients due to one single product and flexible number of injections (1-3 daily) which covers the demand in controlling fasting and postprandial glucose excursions of most patients with diabetes. However, the use of pre-mixed insulin frequently leads to a high insulin demand and consequently weight gain and an increased risk of hypoglycemia. Hence, achieve good metabolic control in these patients remains a major challenge. For those patients, the approach to treatment intensification without facing the typical risks of insulin treatment (hypoglycemia and weight increase) is of major importance. One, so far not exploited option may be the BIT-strategy: Basal insulin in combination with incretin-based therapy. Pathophysiologically basal insulin inhibits glucose production in the liver, decreases hepatic insulin resistance and improves the function of beta cells in the postprandial state by discharge of fasting insulin secretion. During further diabetes progression steadily increasing HbA1c levels - despite good fasting blood glucose control - indicate the need for additional intervention of meal-related glucose excursions. In this stage of type-2 diabetes basal insulin can be combined with prandial (short-acting) insulin or prandial GLP-1 receptor agonists. However, regarding important safety parameters: risks of hypoglycemia and weight gain in the long-term treatment GLP-1 receptor agonists are beneficial. Lixisenatide is a novel GLP-1 receptor agonist with a pronounced postprandial (PPG) effect which fits with basal insulin mode of action primarily focused on fasting blood glucose reduction. Therefore 10 patients (both gender) under treatment with premixed insulin (2-3 times daily) and HbA1c>7% will be switched to basal insulin glargine (Lantus, once daily) and GLP-1 receptor agonist Lixisenatide (Lyxumia, once daily). The investigators hypothesize that switching from a therapy based on premixed insulin to a simple, once daily administered combination of basal insulin plus a GLP-1 receptor agonist in patients with type-2 diabetes not achieving therapeutic target (HbA1c>7%) is clinically feasable in an out patient setting

Official Title
-----------------
Feasibility of Once-daily Administered GLP-1 Receptoragonist (Lixisenatide) in Combination With Basal Insulin in Patients With Type-2 Diabetes Mellitus Not Achieving Therapeutic Targets With Premixed Insulin

Conditions
-----------------
Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: Lixisenatide
* Drug: Insulin glargine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18 - 70a Subjects understand study related activities and give written informed concent HbA1c between 7 - 10 % under treatment with premixed insulin (2-3 injections) Exclusion Criteria: Females of child-bearing age History of hypoglycemia unawareness Gastrointestinal disease associated with prolonged nausea and vomiting Impaired liver function (transaminase >2x than normal) Impaired kidney function (creatinin > 1,2 mg/dl) Known intolerance against GLP-1 receptor agonists History of pancreatitis or pancreas tumor Malignancies, autoimmune diseases Severe dyslipidemia (serum triglycerides > 400 mg/dl, cholesterol > 300 mg/dl) Psychiatric disorder Oral glucose lowering medication except for metformin

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group<br>10 type 2 diabetic patients will be included to perform in this study and will be switched from premixed insulin to insulin glargine and lixisenatide | Drug: Lixisenatide<br>* Patients will be switched to basal insulin glargine (Lantus, once daily in the morning) and GLP-1 receptor agonist Lixisenatide (Lyxumia, once daily in the morning before breakfast; days 1-14 10 µg thereafter 20 µg). The (mean) daily dose of premixed insulin will be calculated based on the records of the run in period. The initial dose of insulin glargine will be adjusted at about 60% of the daily insulin dose of premixed insulin. This is based on the observed reduction of required insulin dose described in recent literature upon initiation with a GLP-1 agonist.<br>* Other names: Lyxumia;Drug: Insulin glargine<br>* Patients will be switched to basal insulin glargine (Lantus, once daily in the morning) and GLP-1 receptor agonist Lixisenatide (Lyxumia, once daily in the morning before breakfast; days 1-14 10 µg thereafter 20 µg). The (mean) daily dose of premixed insulin will be calculated based on the records of the run in period. The initial dose of insulin glargine will be adjusted at about 60% of the daily insulin dose of premixed insulin. This is based on the observed reduction of required insulin dose described in recent literature upon initiation with a GLP-1 agonist.<br>* Other names: Lantus;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c From Baseline to End | A change between two time points is reported. Time Frame: baseline and 12 weeks. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fasting Plasma Glucose (FPG, Mean Over 2 Weeks) | Patients will be instructed to record all insulin injections and a complete 7-point-blood glucose profile (fasting, 2h after breakfast, before lunch, 2h after lunch, before dinner, 2h after dinner, late before going to bed) during a one-week prestudy run-in period to confirm compliance and document current metabolic control and doses of premixed insulin. Patients will be asked to record not only glucose profiles (at least 4 measurements per day) but also the occurrence of hypoglycemic symptoms or other adverse effects daily throughout the study. During the last week of the study patients will be asked to again record a complete 7-point-blood glucose profile (fasting, 2h after breakfast, before lunch, 2h after lunch, before dinner, 2h after dinner, late before going to bed) and drug injections to confirm compliance and document metabolic control. | 12 weeks | 
| Change in Body Weight From Baseline to End of Study | A change between two time points is reported. Time Frame: baseline and 12 weeks. | 12 weeks |