Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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The primary objective of this study is to show that a prandial insulin regimen, consisting of premeal insulin lispro mid mixture (or a combined regimen of insulin lispro mid mixture and insulin lispro low mixture) plus metformin will result in significantly better overall glycemic control (lower HbA1c) at endpoint than once-daily insulin glargine plus metformin. Insulin lispro mid mixture consists of 50% insulin lispro and 50% NPL. Insulin lispro low mixture consists of 25% insulin lispro and 75% NPL. In a substudy of approximately 60 patients, additional data will be collected on markers associated with risk of atherosclerosis or cardiovascular disease in the context of a controlled, outpatient, high-fat test meal.

Official Title
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Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes: A Comparison of Premeal Insulin Lispro Mixtures to Once-Daily Insulin Glargine

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: premeal insulin lispro mixtures
* Drug: insulin glargine
* Drug: metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have type 2 diabetes (World Health Organization [WHO] classification Have used one or more of the following oral anti-hyperglycemic medications-metformin or second-generation sulfonylurea (for example, glibenclamide, glyburide, glipizide, gliclazide, glimepiride) alone or in combination with one or two insulin injections per day for at least 3 months immediately prior to entering the study. Patients using more than 2 insulin injections per day or subcutaneous insulin infusion prior to the study will not be eligible to participate. Have a hemoglobin A1c between 6.5% and 11%, inclusive, according to the central laboratory at Visit 1. Have clinically acceptable LDL-C, in the investigator's opinion, at Visit 1. As determined by the investigator, are capable and willing to learn how to use the insulin injection pens; comply with their prescribed diet, exercise, and medication regimen; perform self-monitoring of blood glucose; and use the patient diary as required for this protocol. Exclusion Criteria: Have hypersensitivity to metformin or a known allergy to metformin hydrochloride, insulin lispro MM, insulin lispro LM, or insulin glargine, or excipients contained in these products. Have known metabolic or lactic acidosis. Have a history of renal transplantation or are currently receiving renal dialysis or have serum creatinine greater than or equal to 135 micromol/L (1.5 mg/dL) for males and greater than or equal to 110 micromol/L (1.2 mg/dL) for females. Have cardiac disease with functional status that is Class III or IV Have obvious clinical signs or symptoms of liver disease, acute or chronic hepatitis, or alanine transaminase (ALT) greater than three times the upper limit of the reference range as defined by the central laboratory.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: premeal insulin lispro mixtures|nan|
|Drug: insulin glargine|nan|
|Drug: metformin|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1C |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| General inflammation (hsCRP) |  |  | 
| High-density lipoprotein cholesterol |  |  | 
| Total cholesterol |  |  | 
| Triglycerides |  |  | 
| Estimates of low-density lipoprotein cholesterol |  |  | 
| Nuclear magnetic resonance [NMR] analysis of lipids |  |  | 
| Oxidized LDL |  |  | 
| Lipoproteins and apoproteins |  |  | 
| Fibrinogen |  |  | 
| Blood glucose levels (based on self-monitoring) |  |  | 
| Insulin dose |  |  | 
| Weight |  |  | 
| Frequency and incidence of hypoglycemia |  |  | 
| Safety |  |  | 
| General well-being |  |  | 
| Pilot two questionnaires for microvascular complications |  |  | 
| Coagulopathy factors [substudy] |  |  | 
| Surrogate measure of vascular reactivity [substudy] |  |  | 
| Inflammatory markers [substudy] |  |  | 
| Production of advanced glycation end-products [substudy] |  |  | 
| Generation of oxidative species [substudy] |  |  | 
| Lipids in various fractions [substudy] |  |  | 
| Retinyl ester measurements in various fractions [substudy] |  |  | 
| Composition of triglyceride-rich lipoproteins [substudy] |  |  | 
| Compartmental modeling of postprandial lipemia [substudy] |  |  | 
| Apolipoproteins [substudy] |  |  |