Diabetic Ketoacidosis
Conditions
Keywords
Diabetic ketoacidosis, insulin therapy, DKA
Brief summary
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
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.
Interventions
DRUGinsulin glargine+ glulisine
Daily insulin glargine + glulisine before meals
DRUGNPH + Regular insulin
Split-mixed NPH + Regular insulin twice daily
Sponsors
Sanofi
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Hypoglycemia Episodes After the Transition Period From Intravenous Insulin to Subcutaneous Insulin Between 2 Treatment Groups | 5 days after transitioning to subcutaneous insulin | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Daily Blood Glucose Concentration Between the Two Groups After the Resolution of Ketoacidosis and Transition to Subcutaneous Insulin | Day1 - Day5 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. |
| Mean Blood Glucose Concentration in mg/dL While on the Insulin Drip Among the 2 Groups | up to 20 hours | 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. |
| Difference in Time in Hours to Resolution of DKA Between the 2 Groups | up to 20 hours | 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. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at Grady Memorial Hospital, Atlanta, Georgia, and at Hennepin County Medical Center, Minneapolis, Minnesota
Pre-assignment details
A total of 74 patients with DKA were randomly assigned. Of them, 6 were excluded because 4 withdrew consent before or shortly after initiation of insulin therapy, one patient received glargine insulin before resolution of DKA, and one patient was treated with IV aspart insulin instead of regular insulin. The remaining 68 were included in analysis
Participants by arm
| Arm | Count |
|---|---|
| Glargine (Lantus) + Glulisine Daily insulin glargine (Lantus) + glulisine (Apidra) before meals | 38 |
| NPH + Regular Split-mixed NPH + Regular insulin twice daily | 36 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
| Overall Study | wrong insulin arm assigned | 1 | 0 |
Baseline characteristics
| Characteristic | NPH + Regular | Glargine (Lantus) + Glulisine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 36 Participants | 38 Participants | 74 Participants |
| Age, Continuous | 38 years STANDARD_DEVIATION 12 | 39 years STANDARD_DEVIATION 12 | 38.5 years STANDARD_DEVIATION 12 |
| Region of Enrollment United States | 36 participants | 38 participants | 74 participants |
| Sex: Female, Male Female | 12 Participants | 14 Participants | 26 Participants |
| Sex: Female, Male Male | 24 Participants | 24 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 38 | 0 / 36 |
| other Total, other adverse events | 5 / 38 | 14 / 36 |
| serious Total, serious adverse events | 1 / 38 | 2 / 36 |
Outcome results
Primary
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.
Time frame: 5 days after transitioning to subcutaneous insulin
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glargine+Glulisine | Number of Hypoglycemia Episodes After the Transition Period From Intravenous Insulin to Subcutaneous Insulin Between 2 Treatment Groups | 8 number of hypoglycemia episodes |
| Split-mixed NPH + Regular Insulin | Number of Hypoglycemia Episodes After the Transition Period From Intravenous Insulin to Subcutaneous Insulin Between 2 Treatment Groups | 26 number of hypoglycemia episodes |
Secondary
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.
Time frame: up to 20 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine+Glulisine | Difference in Time in Hours to Resolution of DKA Between the 2 Groups | 8.9 hours | Standard Deviation 4.7 |
| Split-mixed NPH + Regular Insulin | Difference in Time in Hours to Resolution of DKA Between the 2 Groups | 10.5 hours | Standard Deviation 6.3 |
Secondary
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.
Time frame: up to 20 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glargine+Glulisine | Mean Blood Glucose Concentration in mg/dL While on the Insulin Drip Among the 2 Groups | 153 mg/dL | Standard Deviation 61 |
| Split-mixed NPH + Regular Insulin | Mean Blood Glucose Concentration in mg/dL While on the Insulin Drip Among the 2 Groups | 185 mg/dL | Standard Deviation 58 |
Secondary
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.
Time frame: Day1 - Day5 after the resolution of ketoacidosis and transition to subcutaneous insulin
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Glargine+Glulisine | Mean Daily Blood Glucose Concentration Between the Two Groups After the Resolution of Ketoacidosis and Transition to Subcutaneous Insulin | Day 1 | 213 mg/dl | Standard Deviation 76 |
| Insulin Glargine+Glulisine | Mean Daily Blood Glucose Concentration Between the Two Groups After the Resolution of Ketoacidosis and Transition to Subcutaneous Insulin | Day 2 | 220 mg/dl | Standard Deviation 61 |
| Insulin Glargine+Glulisine | Mean Daily Blood Glucose Concentration Between the Two Groups After the Resolution of Ketoacidosis and Transition to Subcutaneous Insulin | Day 3 | 180 mg/dl | Standard Deviation 80 |
| Insulin Glargine+Glulisine | Mean Daily Blood Glucose Concentration Between the Two Groups After the Resolution of Ketoacidosis and Transition to Subcutaneous Insulin | Day 5 | 124 mg/dl | Standard Deviation 41 |
| Insulin Glargine+Glulisine | Mean Daily Blood Glucose Concentration Between the Two Groups After the Resolution of Ketoacidosis and Transition to Subcutaneous Insulin | Day 4 | 158 mg/dl | Standard Deviation 44 |
| Split-mixed NPH + Regular Insulin | Mean Daily Blood Glucose Concentration Between the Two Groups After the Resolution of Ketoacidosis and Transition to Subcutaneous Insulin | Day 3 | 207 mg/dl | Standard Deviation 86 |
| Split-mixed NPH + Regular Insulin | Mean Daily Blood Glucose Concentration Between the Two Groups After the Resolution of Ketoacidosis and Transition to Subcutaneous Insulin | Day 1 | 188 mg/dl | Standard Deviation 61 |
| Split-mixed NPH + Regular Insulin | Mean Daily Blood Glucose Concentration Between the Two Groups After the Resolution of Ketoacidosis and Transition to Subcutaneous Insulin | Day 4 | 211 mg/dl | Standard Deviation 63 |
| Split-mixed NPH + Regular Insulin | Mean Daily Blood Glucose Concentration Between the Two Groups After the Resolution of Ketoacidosis and Transition to Subcutaneous Insulin | Day 2 | 206 mg/dl | Standard Deviation 71 |
| Split-mixed NPH + Regular Insulin | Mean Daily Blood Glucose Concentration Between the Two Groups After the Resolution of Ketoacidosis and Transition to Subcutaneous Insulin | Day 5 | 190 mg/dl | Standard Deviation 45 |