Basal Insulin in the Management of Patients With Diabetic Ketoacidosis (DKA)

Study Overview
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Brief Summary
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The study is a multicenter, randomized controlled trial to compare the safety and efficacy of insulin analogs and human insulins both during acute intravenous treatment and during the transition to subcutaneous insulin in patients with diabetic ketoacidosis (DKA).

Detailed Description
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Diabetic ketoacidosis (DKA) is the most serious emergency in patients with diabetes. With an estimated 100,000 admissions per year in the United States, DKA is also the leading cause of death in children with type 1 diabetes, and accounts for a significant proportion of admissions in adult patients with type 1 and type 2 diabetes. The mainstay in the treatment of DKA involves the continuous intravenous (IV) infusion of regular insulin or the frequent subcutaneous (SC) injections of regular or rapid-acting insulin analogs. Multiple studies have reported successful protocols for insulin administration during the acute management of DKA, but they have failed to address the transition phase from IV to SC maintenance insulin regimen. The American Diabetes Association (ADA) position statement recommends the use of split-mixed insulin combination of regular and intermediate-acting insulin (NPH). This regimen, however, are associated with a high rate of hyperglycemia shortly after discontinuation of IV insulin and a risk of hypoglycemia during the hospital stay. Recently, the long-acting basal insulin glargine (Lantus®, Sanofi Aventis Pharmaceuticals) has been shown to facilitate glycemic control with lower rate of hypoglycemic events than intermediate-acting insulin in subjects with type 1 and type 2 diabetes. This study aims i) to determine the effects of giving a dose of glargine insulin shortly after starting an intravenous insulin infusion on glycemic control, time to resolve DKA, and rate of hypoglycemia in patients with DKA, and ii) to compare the safety and efficacy of basal/bolus (glargine/glulisine) insulin versus the standard split-mixed insulin regimen of NPH and regular insulin after the resolution of DKA. The hypothesis is that basal (lantus®) insulin as compared to NPH insulin shortly after the start of insulin infusion will improve inpatient glycemic control in patients with DKA.

Official Title
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Basal Insulin in the Management of Patients With Diabetic Ketoacidosis

Conditions
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Diabetic Ketoacidosis

Intervention / Treatment
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* Drug: insulin glargine+ glulisine
* Drug: NPH + Regular insulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients admitted to Grady Memorial Hospital who meet diagnosis criteria of DKA and who are willing to participate in the study protocol will be considered candidates for inclusion into the study. Diagnostic Criteria for DKA: Blood glucose > 250 mg/dL, arterial or venous phenol hydroxylase (pH) < 7.3, serum bicarbonate < 18 milliequivalent/L, and moderate to severe ketonemia (acetoacetate ≥ 1:4 or βeta-hydroxybutyrate > 3 mmol). Exclusion Criteria: Hemodynamic instability (MAP < 50 or patients requiring pressor) Significant identifiable medical or surgical illness, including but not limited to: acute myocardial infarction, congestive heart failure; respiratory failure requiring mechanical ventilation; acute or chronic renal insufficiency (serum creatinine > 3.0 mg/dl); end stage liver failure, and cirrhosis. Patients with dementia or persistent altered mental status that would prevent collection of consent form and reliable information. Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulin glargine+glulisine<br>Daily insulin glargine + glulisine before meals | Drug: insulin glargine+ glulisine<br>* Daily insulin glargine + glulisine before meals<br>* Other names: glargine (Lantus) + glulisine (Apidra);|
| Active Comparator: Split-mixed NPH + Regular insulin<br>Split-mixed NPH + Regular insulin twice daily | Drug: NPH + Regular insulin<br>* Split-mixed NPH + Regular insulin twice daily<br>* Other names: Intermediate acting Insulin (NPH);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Hypoglycemia Episodes After the Transition Period From Intravenous Insulin to Subcutaneous Insulin Between 2 Treatment Groups | To determine the safety of the two treatments the number of hypoglycemia episodes that occurred between the 2 groups are measured from the time of transitioning to subcutaneous insulin to day 5. The hypoglycemia events are defined as blood glucose levels <70 mg/dL. The results were obtained from the citation Umpierrez GE, Jones S, Smiley D, Mulligan P, Keyler T, Temponi A, Semakula C, Umpierrez D, Peng L, Cerón M, Robalino G. Insulin analogs versus human insulin in the treatment of patients with diabetic ketoacidosis: a randomized controlled trial. Diabetes Care. 2009 Jul;32(7):1164-9. doi: 10.2337/dc09-0169. Epub 2009 Apr 14. PubMed ID: 19366972. | 5 days after transitioning to subcutaneous insulin | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Daily Blood Glucose Concentration Between the Two Groups After the Resolution of Ketoacidosis and Transition to Subcutaneous Insulin | The primary outcome during the subcutaneous (SC) period (the primary outcome measurement) was to determine differences in glycemic control as measured by mean daily blood glucose(BG) concentration between treatment groups. The results were obtained from the citation Umpierrez GE, Jones S, Smiley D, Mulligan P, Keyler T, Temponi A, Semakula C, Umpierrez D, Peng L, Cerón M, Robalino G. Insulin analogs versus human insulin in the treatment of patients with diabetic ketoacidosis: a randomized controlled trial. Diabetes Care. 2009 Jul;32(7):1164-9. doi: 10.2337/dc09-0169. Epub 2009 Apr 14. PubMed Identification (ID): 19366972. | Day1 - Day5 after the resolution of ketoacidosis and transition to subcutaneous insulin | 
| Mean Blood Glucose Concentration in mg/dL While on the Insulin Drip Among the 2 Groups | To determine the differences in glycemic control as measured by differences in the mean daily blood glucose levels between treatment groups (insulin drip with regular insulin vs glulisine insulin) during the acute phase of diabetic ketoacidosis(DKA) before transitioning to subcutaneous insulin. The results were obtained from the citation Umpierrez GE, Jones S, Smiley D, Mulligan P, Keyler T, Temponi A, Semakula C, Umpierrez D, Peng L, Cerón M, Robalino G. Insulin analogs versus human insulin in the treatment of patients with diabetic ketoacidosis: a randomized controlled trial. Diabetes Care. 2009 Jul;32(7):1164-9. doi: 10.2337/dc09-0169. Epub 2009 Apr 14. PubMed ID: 19366972. | up to 20 hours | 
| Difference in Time in Hours to Resolution of DKA Between the 2 Groups | The mean duration of treatment until resolution of ketoacidosis is measured and compared between the 2 groups. The DKA was considered resolved when blood glucose was 250 mg/dl, the serum bicarbonate level was <18 mmol/l, and venous phenol hydroxylase (pH) was 7.30. The results were obtained from the citation Umpierrez GE, Jones S, Smiley D, Mulligan P, Keyler T, Temponi A, Semakula C, Umpierrez D, Peng L, Cerón M, Robalino G. Insulin analogs versus human insulin in the treatment of patients with diabetic ketoacidosis: a randomized controlled trial. Diabetes Care. 2009 Jul;32(7):1164-9. doi: 10.2337/dc09-0169. Epub 2009 Apr 14. PubMed ID: 19366972. | up to 20 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetic ketoacidosis, insulin therapy, DKA